Method for the regioselective preparation of substituted benzo[g]quinoline-3-carbonitriles and benzo[g]quinazolines

ABSTRACT

This invention relates to a method for the regioselective synthesis of 4,6,7,8-substituted benzo[g]quinoline-3-carbonitriles and 4,6,7,8-substituted benzo[g]quinazolines as well as intermediates thereof. The compounds derived from this invention are useful for the treatment of a variety of diseases that are a result of deregulation of these PTK&#39;s, and more specifically, are anti-cancer agents and are useful for the treatment of cancer in mammals. In addition, the compounds derived from this invention are useful for the treatment of polycystic kidney disease in mammals.

This application under 35 U.S.C. § 371(c) is based on InternationalApplication No. PCT/US01/47939, filed on Dec. 11, 2001 and claimspriority under 35 U.S.C. § 119(e) of U.S. Provisional Application No.60/259,190 filed on Dec. 29, 2000, abandoned, the entire disclosure ofwhich is hereby incorporated by reference.

FIELD OF THE INVENTION

This invention relates to a method for the regioselective synthesis of4,6,7,8-substituted benzo[g]quinoline-3-carbonitriles and4,6,7,8-substituted benzo[g]quinazolines as well as intermediatesthereof. The compounds derived from this invention are useful for thetreatment of a variety of diseases that are a result of deregulation ofthese PTK's, and more specifically, are anti-cancer agents and areuseful for the treatment of cancer in mammals. In addition, thecompounds derived from this invention are useful for the treatment ofpolycystic kidney disease in mammals.

BACKGROUND OF THE INVENTION

Certain 4-anilino-benzo[g]quinoline-3-carbonitriles as protein kinaseinhibitors are disclosed in PCT patent application WO0147892.

Certain 4-anilino-benzo[g]quinazolines as protein kinase inhibitors aredisclosed in several patents and publications: WO9749688, U.S. Pat. No.5,679,683, WO9519970, WO9713760 and J. Med. Chem. 1996, 39, 918-928.These references disclose that 4-anilino-benzo[g]quinazolines and4-anilin-benzo[g]quinoline-3-carbonitriles possess potent activity asprotein kinase inhibitors.

Throughout this patent application, the benzo[g]quinoline ring systemwill be numbered as indicated in the formula below:

Throughout this patent application, the benzo[g]quinazoline ring systemwill be numbered as indicated in the formula below:

SUMMARY OF THE INVENTION

The present invention relates to a process for the production of6,7,8-substituted 3-amino-2-naphthoates or 3-amino-2-naphthonitriles offormula (A)

wherein

-   E is cyano or E is an alkoxycarbonyl of 2-12 carbons, —CO₂-Ph,    —CO₂-L, cycloalkoxycarbonyl of 4-12 carbons, alkenyloxycarbonyl of    3-12 carbons, cycloalkenyloxycarbonyl of 5-12 carbons,    alkynyloxycarbonyl of 4-12 carbons, which may be optionally    substituted on a carbon atom with one or more R₆ groups;-   R₁, R₂ and R₃ are each, independently, hydrogen, halogen, hydroxy,    amino, hydroxyamino, trifluoromethyl, trifluoromethoxy, mercapto,    alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl    of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6    carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxyalkyl of 1-6    carbon atoms, mercaptoalkyl of 1-6 carbon atoms, halomethyl,    alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,    cycloalkoxy of 3-8 carbon atoms, alkylthio of 1-6 carbon atoms,    cycloalkylthio of 3-8 carbon atoms, alkylsulphinyl of 1-6 carbon    atoms, alkylsulfonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6    carbon atoms, alkenylsulfonamido of 2-6 carbon atoms,    alkynylsulfonamido of 2-6 carbon atoms, cyano, nitro, carboxy,    alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms,    alkenoyl of 3-7 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12    carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino,    benzylamino, phenoxy, phenyl, thiophenoxy, benzyl, alkylamino of 1-6    carbon atoms, alkanoyloxy of 2-7 carbon atoms, alkenoyloxy of 3-8    carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,    N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13    carbon atoms, dialkylamino of 2 to 12 carbon atoms,    alkanoyloxymethyl group of 2-7 carbon atoms, alkenoyloxymethyl group    of 2-7 carbon atoms, alkynoyloxymethyl group of 2-7 carbon atoms,    azido, benzoyl, carboxyalkyl of 2-7 carbons, carboalkoxyalkyl of 3-8    carbon atoms,

-   R₅ is independently hydrogen, alkyl of 1-6 carbon atoms, aminoalkyl    of 1-6 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms,    N,N-dialkylaminoalkyl of 3-12 carbon atoms, N-cycloalkylaminoalkyl    of 4-12 carbon atoms, N-cycloalkyl-N-alkylaminoalkyl of 5-18 carbon    atoms, N,N-dicycloalkylaminoalkyl of 7-18 carbon atoms,    morpholino-N-alkyl wherein the alkyl group is 1-6 carbon atoms,    piperidino-N-alkyl wherein the alkyl group is 1-6 carbon atoms,    N-alkyl-piperazino-N-alkyl wherein either alkyl group is 1-6 carbon    atoms, azacycloalkyl-N-alkyl of 3-11 carbon atoms, hydroxyalkyl of    1-6 carbon atoms, alkoxyalkyl of 2-8 carbon atoms, phenyl;-   V is (CH₂)_(m), O, S, or NR₆;-   R₇ is NR₆R₆, OR₆, J, N(R₆)₃ ⁺, or NR₆(OR₆);-   M is NR₆, O, S, N—[(C(R₆)₂)_(p)NR₆R₆], or N—[(C(R₆)₂)_(p)—OR₆];-   W is NR₆, O, S, or is a bond;-   Het is a heterocycle selected from the group consisting of    morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine    S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine,    imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine,    tetrazole, piperazine, furan, thiophene, tetrahydrothiophene,    tetrahydrofuran, dioxane, 1,3-dioxolane pyrrole, and    tetrahydropyran; wherein the heterocycle is optionally mono- or    di-substituted on carbon or nitrogen with R₆; optionally mono- or    di-substituted on carbon with hydroxy, —N(R₆)₂, or —OR₆; optionally    mono or di-substituted on carbon with the mono-valent radicals    —(C(R₆)₂)_(s)OR₆ or —[(C(R₆)₂)_(s)N(R₆)₂]; or optionally mono or    di-substituted on a saturated carbon with divalent radicals ═O or    —O(C(R₆)₂)_(s)O—;-   Ph is a phenyl ring optionally mono-, di- or tri-substituted with    halogen, alkyl of 1-6 carbon atoms, trifluoromethyl, nitro, cyano,    azido, halomethyl, carboxyl, alkoxycarbonyl, alkylthio, mercapto,    mercaptomethyl, —N(R₆)₂, —OR₆, (C(R₆)₂)_(s)OR₆,    —[(C(R₆)₂)_(s)N(R₆)₂], or —(C(R₆)₂)_(k)Het;-   R₆ is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon    atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms,    alkanoyl of 2-7 carbon atoms, carbamoylalkyl of 2-7 carbon atoms,    hydroxyalkyl of 1-6 carbon atoms, hydroxycycloalkyl of 3-6 carbon    atoms, or carboxyalkyl of 2-7 carbon atoms; or-   R₆ is phenyl optionally mono-, di-, or tri-substituted with halogen,    alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of    1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano,    azido, halomethyl, alkoxymethyl of 2-7 carbon atoms,    alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon    atoms, hydroxy, carboxyl, alkoxycarbonyl of 2-7 carbon atoms,    phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino,    benzylamino; alkanoylamino of 1-6 carbon atoms or alkyl of 1-6    carbon atoms;-   R₈ and R₉ are each, independently, —[(C(R₆)₂)_(r)NR₆R₆], or    —[(C(R₆)₂)_(r)OR₆];-   J is independently hydrogen, chlorine, fluorine, or bromine;-   g=1-6;-   k=0-4;-   p=2-4;-   q=0-4;-   r=1-4;-   s=1-6;-   m is 0-3;    which process comprises:-   (a) reacting a substituted    bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile of formula 1

-   -   wherein R₁, R₂, and R₃ are defined as above;    -   with a base to form a first intermediate having the        corresponding anion alpha to the cyano group;

-   (b) reacting said first intermediate with a suitable electrophilic    sulfur group to yield an alpha-sulfenylated 1-cyanobenzocyclobutene    of formula 2

-   -   wherein R₁, R₂, R₃, and Ph are defined as above;

-   (c) reacting an anionic salt of an alkyl or aryl ester or    acetonitrile with said cyanobenzocyclobutenes of formula 2 to    provide an amino ester or amino nitrile intermediate of formula 3

wherein R₁, R₂, R₃, Ph, and E are defined as above; and

-   (d) refluxing the formula 3 adducts in a solvent to provide the    substituted esters or nitriles of formula A.

The invention also relates to certain related processes to makesubstituted benzo[g]quinoline-3-carbonitriles and benzo[g]quinazolinesand certain intermediates formed in the aforementioned processes.

DESCRIPTION OF THE INVENTION

The invention provides a novel method for the synthesis of6,7,8-substituted 3-amino-2-naphthoates or 3-amino-2-naphthonitriles(A), 4,6,7,8-substituted benzo[g]quinoline-3-carbonitriles (B) and4,6,7,8-substituted benzo[g]quinazolines (C) with complete regiochemicalcontrol and in high yields. This constitutes a significant advantageover previously described methods. From the key intermediate A, thecompounds B and C can be constructed as single geometric isomers.

Wherein:

-   E is cyano or E is an alkoxycarbonyl of 2-12 carbons, —CO₂Ph,    —CO₂-L, cycloalkoxycarbonyl of 4-12 carbons, alkenyloxycarbonyl of    3-12 carbons, cycloalkenyloxycarbonyl of 5-12 carbons,    alkynyloxycarbonyl of 4-12 carbons, which may be substituted on a    carbon atom with one or more R₆ groups;-   Ar is cycloalkyl of 3 to 7 carbon atoms, which may be optionally    substituted with one or more alkyl of 1 to 6 carbon atoms; or-   Ar is a pyridinyl, pyrimidinyl, or phenyl ring; wherein the    pyridinyl, pyrimidinyl, or phenyl ring may be optionally mono-, di-,    or tri-substituted with substituent(s) independently selected from    the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl    of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido,    hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7    carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6    carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy,    trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon    atoms, alkanoyl of 2-7 carbon atoms, benzoyl, amino, alkylamino of    1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms,    alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon    atoms, alkynoylamino of 3-8 carbon atoms, alkanoyloxy of 1-6 carbon    atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon    atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,    N,N-dialkylcarbamoyl of 3-13 carbon atoms, carboxyalkyl of 2-7    carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of    1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms,    N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of    3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms,    mercapto, methylmercapto and benzoylamino; or-   Ar is a bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12    atoms where the bicyclic heteroaryl ring may contain 1 to 4    heteroatoms selected from N, O, and S wherein the bicyclic aryl or    bicyclic heteroaryl ring may be optionally mono- di-, tri, or    tetra-substituted with substituent(s) independently selected from    the group consisting of halogen, oxo, thiocarbonyl, alkyl of 1-6    carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon    atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl,    alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon    atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms,    hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of    2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, phenoxy, phenyl,    thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms,    dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino,    alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon    atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon    atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5    carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms,    N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of    3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms,    mercapto, methylmercapto, alkanoyloxy of 1-6 carbon atoms,    alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms,    carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,    N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; or-   Ar is the radical:

-   A′ is a pyridinyl, pyrimidinyl, or phenyl ring; wherein the    pyridinyl, pyrimidinyl, or phenyl ring may be optionally mono- or    di-substituted with substituent(s) independently selected from the    group consisting of alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon    atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6    carbon atoms, halogen, halomethyl, alkoxymethyl of 2-7 carbon atoms,    alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,    alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,    nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7    carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino,    alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon    atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms,    alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon    atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8    carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of    2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms,    N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of    4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6    carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8    carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,    N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino;-   T is substituted on A′ at carbon and is —NH(CH₂)_(m)—, —(CH₂)_(m)—,    —S(CH₂)_(m)—, —NR(CH₂)_(m)—, —(CH₂)_(m)—, —(CH₂)_(m)NH—,    —(CH₂)_(m)O—, —(CH₂)_(m)S—, —SO(CH₂)_(m)—, —SO₂(CH₂)_(m)—,    —CO(CH₂)_(m)—, —(CH₂)_(m)CO—, —(CH₂)_(m)SO—, —(CH₂)_(m)SO₂— or    —(CH₂)_(m)NR—;-   L is a phenyl ring that is optionally substituted with one, two, or    three substituent(s) independently selected from the group    consisting of alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon    atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6    carbon atoms, halogen, halomethyl, alkoxymethyl of 2-7 carbon atoms,    alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,    alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,    nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7    carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino,    alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon    atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms,    alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon    atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8    carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of    2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms,    N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of    4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6    carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8    carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,    N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; or-   L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring    contains 1 to 3 heteroatom(s) independently selected from N, O, and    S and where the heteroaryl ring may be optionally mono- or    di-substituted with substituent(s) independently selected from the    group consisting of halogen, oxo, thiocarbonyl, alkyl of 1-6 carbon    atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms,    azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of    2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of    1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy,    trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon    atoms, alkanoyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy,    benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino    of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of    1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino    of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms,    carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon    atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl    of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms,    N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto,    methylmercapto, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8    carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,    N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13    carbon atoms, and benzoylamino;-   m is 0-3;-   n is 0-1;-   X is NH, O, S, or NR;-   R is alkyl of 1-6 carbon atoms;-   R₁, R₂ and R₃ are each, independently, hydrogen, halogen, hydroxy,    amino, arylamino, arylalkylamino, hydroxyamino, trifluoromethyl,    trifluoromethoxy, mercapto, alkyl of 1-6 carbon atoms, cycloalkyl of    3-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon    atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon    atoms, hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of 1-6 carbon    atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6    carbon atoms, cycloalkoxy of 3-8 carbon atoms, alkylthio of 1-6    carbon atoms, cycloalkylthio of 3-8 carbon atoms, alkylsulphinyl of    1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms,    alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6    carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, cyano, nitro,    carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon    atoms, alkenoyl of 3-7 carbon atoms, N-alkyl-N-alkenylamino of 4 to    12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms,    phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy, benzyl,    alkylamino of 1-6 carbon atoms, alkanoyloxy of 2-7 carbon atoms,    alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms,    carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,    N,N-dialkylcarbamoyl of 3-13 carbon atoms, dialkylamino of 2 to 12    carbon atoms, alkanoyloxymethyl group of 2-7 carbon atoms,    alkenoyloxymethyl group of 2-7 carbon atoms, alkynoyloxymethyl group    of 2-7 carbon atoms, azido, benzoyl, carboxyalkyl of 2-7 carbons,    carboalkoxyalkyl of 3-8 carbon atoms,

-   R₅ is independently hydrogen, alkyl of 1-6 carbon atoms, aminoalkyl    of 1-6 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms,    N,N-dialkylaminoalkyl of 3-12 carbon atoms, N-cycloalkylaminoalkyl    of 4-12 carbon atoms, N-cycloalkyl-N-alkylaminoalkyl of 5-18 carbon    atoms, N,N-dicycloalkylaminoalkyl of 7-18 carbon atoms,    morpholino-N-alkyl wherein the alkyl group is 1-6 carbon atoms,    piperidino-N-alkyl wherein the alkyl group is 1-6 carbon atoms,    N-alkyl-piperazino-N-alkyl wherein either alkyl group is 1-6 carbon    atoms, azacycloalkyl-N-alkyl of 3-11 carbon atoms, hydroxyalkyl of    1-6 carbon atoms, alkoxyalkyl of 2-8 carbon atoms, phenyl;-   V is (CH₂)_(m), O, S, or NR₆;-   R₇ is NR₆R₆, OR₆, J, N(R₆)₃ ⁺, or NR₆(OR₆);-   M is NR₆, O, S, N—[(C(R₆)₂)_(p)NR₆R₆], or N—[(C(R₆)₂)_(p)—OR₆];-   W is NR₆, O, S, or is a bond;-   Het is a heterocycle selected from the group consisting of    morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine    S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine,    imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine,    tetrazole, piperazine, furan, thiophene, tetrahydrothiophene,    tetrahydrofuran, dioxane, 1,3-dioxolane pyrrole, and    tetrahydropyran; wherein the heterocycle is optionally mono- or    di-substituted on carbon or nitrogen with R₆; optionally mono- or    di-substituted on carbon with hydroxy, —N(R₆)₂, or —OR₆; optionally    mono or di-substituted on carbon with the mono-valent radicals    —(C(R₆)₂)_(s)OR₆ or —[(C(R₆)₂)_(s)N(R₆)₂]; or optionally mono or    di-substituted on a saturated carbon with divalent radicals ═O or    —O(C(R₆)₂)_(s)O—;-   Ph is a phenyl ring optionally mono-, di- or tri-substituted with    halogen, alkyl of 1-6 carbon atoms, trifluoromethyl, nitro, cyano,    azido, halomethyl, carboxyl, alkoxycarbonyl, alkylthio, mercapto,    mercaptomethyl, —N(R₆)₂, —OR₆, —(C(R₆)₂)_(s)OR₆,    —[(C(R₆)₂)_(s)N(R₆)₂], or —(C(R₆)₂)_(k)Het;-   R₆ is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon    atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms,    alkanoyl of 2-7 carbon atoms, carbamoylalkyl of 2-7 carbon atoms,    hydroxyalkyl of 1-6 carbon atoms, hydroxycycloalkyl of 3-6 carbon    atoms, or carboxyalkyl of 2-7 carbon atoms; or-   R₆ is phenyl optionally mono-, di-, or tri-substituted with halogen,    alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of    1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano,    azido, halomethyl, alkoxymethyl of 2-7 carbon atoms,    alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon    atoms, hydroxy, carboxyl, alkoxycarbonyl of 2-7 carbon atoms,    phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino,    benzylamino; alkanoylamino of 1-6 carbon atoms or alkyl of 1-6    carbon atoms;-   R₈ and R₉ are each, independently, —[(C(R₆)₂)_(r)NR₆R₆], or    —[(C(R₆)₂)_(r)OR₆];-   J is independently hydrogen, chlorine, fluorine, or bromine;-   g=1-6;-   k=0-4;-   p=2-4;-   q=0-4;-   r=1-4;-   s=1-6;    or a pharmaceutically acceptable salt thereof;-   provided that when R₅ is bound to a nitrogen atom, the resulting    structures do not include —N—C—N— or —O—C—N— radicals; and when R₅    is bound to an oxygen atom, the resulting structures do not include    an —N—C— radical;-   provided that when R₆ is alkenyl of 2-7 carbon atoms or alkynyl of    2-7 carbon atoms, the alkenyl or alkynyl moieties are bound to a    nitrogen or oxygen atom through a saturated carbon atom in the    alkenyl or alkynyl chain;-   provided that when V is NR₆ and R₇ is NR₆R₆, N(R₆)₃ ⁺, or NR₆(OR₆),    then g=2-6;-   provided that when M is O or S and R₇ is OR₆, then p=1-4;-   provided that when V is NR₆, O, S, then k=2-4;-   provided that when V is O or S and M or W is O or S, then k=1-4-   provided that when W is not a bond with Het bonded through a    nitrogen atom then q=2-4; and-   finally provided when W is a bond with Het bonded through a nitrogen    atom and V is O or NR₆ or S, then k=2-4.

The pharmaceutically acceptable salts are any salts conventionally usedin the pharmaceutical industry including those derived from such organicand inorganic acids such as: acetic, lactic, citric, tartaric, succinic,maleic, malonic, gluconic, hydrochloric, hydrobromic, phosphoric,nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.

It is understood by one skilled in the art that the heteroaryl orbicyclic heteroaryl rings of the compounds of Formula I do not containO—O, S—S, or S—O bonds, as they would be unstable. Preferred bicyclicaryl or bicyclic heteroaryl ring systems include naphthalene, tetralin,indan, 1-indanone, 1,2,3,4-tetrahydroquinoline, naphthyridine,benzofuran, 3-oxo-1,3-dihydroisobenzofuran, benzothiophene,1,1-dioxo-benzothiophene, indole, indoline1,3-dioxo-2,3-dihydro-1H-isoindole, benzotriazole, 1H-indazole,indoline, indazole, 1,3-benzodioxole, benzoxazole, purine, phthalimide,coumarin, chromone, quinoline, terahydroquinoline, isoquinoline,benzimidazole, quinazoline, pyrido[2,3-b]pyridine, pyrido[3,4b]pyrazine,pyrido[3,2-c]pyridazine, pyrido[3,4-b]pyridine,1H-pyrazole[3,4-d]pyrimidine, 1,4-benzodioxane, pteridine,2(1H)-quinolone, 1(2H)-isoquinolone, 2-oxo-2,3-dihydrobenzthiazole,1,2-methylenedioxybenzene, 2-oxindole, 1,4-benzisoxazine, benzothiazole,quinoxaline, quinoline-N-oxide, isoquinoline-N-oxide,quinoxaline-N-oxide, quinazoline-N-oxide, benzoazine, phthalazine,1,4-dioxo-1,2,3,4-tetrahydrophthalazine, 2-oxo-1,2-dihydroquinoline,2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine,2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine, or cinnoline.

When L is a 5 or 6-membered heteroaryl ring, preferred heteroaryl ringsare pyridine, pyrimidine, imidazole, thiazole, thiazolidine, pyrrole,furan, thiophene, oxazole, or 1,2,4-triazole.

Either or both rings of the bicyclic aryl or bicyclic heteroaryl groupmay be fully unsaturated, partially saturated, or fully saturated. Anoxo substituent on the bicyclic aryl or bicyclic heteroaryl moiety meansthat one of the carbon atoms has a carbonyl group. A thiocarbonylsubstituent on the bicyclic aryl or bicyclic heteroaryl moiety meansthat one of the carbon atoms has a thiocarbonyl group.

When L is a 5 or 6-membered heteroaryl ring, it may be fullyunsaturated, partially saturated, or fully saturated. The heteroarylring can be bound to A′ via carbon or nitrogen. An oxo substituent onthe heteroaryl ring means that one of the carbon atoms has a carbonylgroup. A thio substituent on the heteroaryl ring means that one of thecarbon atoms has a thiocarbonyl group.

The alkyl portion of the alkyl, alkoxy, alkanoyloxy, alkoxymethyl,alkanoyloxymethyl, alkylsulphinyl, alkylsulfonyl, alkylsulfonamido,alkoxycarbonyl, carboxyalkyl, carboalkoxyalkyl, alkanoylamino,N-alkylcarbamoyl, N,N-dialkylcarbamoyl, N-alkylaminoalkoxy andN,N-dialkylaminoalkoxy include both straight chain as well as branchedcarbon chains. The cycloalkyl portions of cycloalkyl, N-cycloalkylamino,N-cycloalkyl-N-alkylaminoalkyl, N,N-dicycloalkylaminoalkyl,cycloalkylthio and azacycloalkyl substituents include both simplecarbocycles as well as carbocycles containing alkyl substituents. Thealkenyl portion of the alkenyl, alkenyloxy, alkenylsulfonamido,substituents include both straight chain as well as branched carbonchains and one or more sites of unsaturation and all possibleconfigurational isomers. The alkynyl portion of the alkynyl,alkynylsulfonamido, alkynyloxy, substituents include both straight chainas well as branched carbon chains and one or more sites of unsaturation.Carboxy is defined as a —CO₂H radical. Alkoxycarbonyl of 2-7 carbonatoms is defined as a —CO₂R″ radical, where R″ is an alkyl radical of1-6 carbon atoms. Carboxyalkyl is defined as a HO₂C—R′″— radical whereR′″ is a divalent alkyl radical of 1-6 carbon atoms. Carboalkoxyalkyl isdefined as a R″O₂C—R′″— radical where R′″ is a divalent alkyl radicaland where R″ and R′″ may be the same or different, and together have 2-7carbon atoms. Alkanoyl is defined as a —COR″ radical, where R″ is analkyl radical of 1-6 carbon atoms. Alkenoyl is defined as a —COR″radical, where R″ is an alkenyl radical of 2-6 carbon atoms. Alkanoyloxyis defined as a —OCOR″ radical, where R″ is an alkyl radical of 1-6carbon atoms. Alkanoyloxymethyl is defined as R″CO₂CH₂— radical, whereR″ is an alkyl radical of 1-6 carbon atoms. Alkoxymethyl is defined asR″OCH₂— radical, where R″ is an alkyl radical of 1-6 carbon atoms.Alkylsulphinyl is defined as R″SO— radical, where R″ is an alkyl radicalof 1-6 carbon atoms. Alkylsulfonyl is defined as R″SO₂-radical, where R″is an alkyl radical of 1-6 carbon atoms. Alkylsulfonamido,alkenylsulfonamido, alkynylsulfonamido are defined as R″SO₂NH— radical,where R″ is an alkyl radical of 1-6 carbon atoms, an alkenyl radical of2-6 carbon atoms, or an alkynyl radical of 2-6 carbon atoms,respectively. N-alkylcarbamoyl is defined as R″NHCO— radical, where R″is an alkyl radical of 1-6 carbon atoms. N,N-dialkylcarbamoyl is definedas R″R′NCO— radical, where R″ is an alkyl radical of 1-6 carbon atoms,R′ is an alkyl radical of 1-6 carbon atoms and R′ and R″ may be the sameor different.

Het is a heterocycle, as defined above which may be optionally mono- ordi-substituted with R₆ on carbon or nitrogen, optionally mono- ordi-substituted on carbon with hydroxy, —N(R₆)₂, or —OR₆, optionally monoor di-substituted on carbon with —(C(R₆)₂)_(s)OR₆ or—(C(R₆)₂)_(s)N(R₆)₂, and optionally mono or di-substituted on asaturated carbon with divalent ═O or —O(C(R₆)₂)_(s)O— (carbonyl andketal groups, respectively); in some cases when Het is substituted with═O (carbonyl), the carbonyl group can be hydrated. Het may be bonded toW when q=0 via a carbon atom on the heterocyclic ring, or when Het is anitrogen containing heterocycle which also contains a saturatedcarbon-nitrogen bond, such heterocycle may be bonded to carbon, via thenitrogen when W is a bond. When q=0 and Het is a nitrogen containingheterocycle which also contains an unsaturated carbon-nitrogen bond,that nitrogen atom of the heterocycle may be bonded to carbon when W isa bond and the resulting heterocycle will bear a positive charge. WhenHet is substituted with R₆, such substitution may be on a ring carbon,or in the case of a nitrogen containing heterocycle, which also containsa saturated carbon-nitrogen, such nitrogen may be substituted with R₆ orin the case of a nitrogen containing heterocycle, which also contains anunsaturated carbon-nitrogen, such nitrogen may be substituted with R₆ inwith case the heterocycle will bear a positive charge. Preferredheterocycles include pyridine, 2,6-disubstituted morpholine,2,5-disubstituted thiomorpholine, 2-substituted imidazole, substitutedthiazole, N-substituted imidazole, N-subsitituted 1,4-piperazine,N-subsitituted piperidine, and N-substituted pyrrolidine.

The compounds of this invention may contain one or more asymmetriccarbons atoms; in such cases, the compounds of this invention includethe individual diasteromers, the racemates, and the individual R and Senantiomers thereof. Some of the compound of this invention may containone or more double bonds; in such cases, the compounds of this inventioninclude each of the possible configurational isomers as well as mixturesof these isomers.

This invention relates to a method for the regioselective synthesis of4,6,7,8-substituted benzo[g]quinoline-3-carbonitriles and4,6,7,8-substituted benzo[g]quinazolines as well as intermediatesthereof. The benzo[g]quinoline-3-carbonitriles and benzo[g]quinazolines,as well as the pharmaceutically acceptable salts thereof, prepared bythe process of this invention inhibit the action of certain growthfactor receptor protein kinases (PTK), thereby inhibiting the abnormalgrowth of certain cell types. Certain 7,8-disubstituted4-anilinobenzo[g]quinoline-3-carbonitriles and their use as anti-canceragents are disclosed in U.S. patent application 09/751,274 filed Dec.29, 2000, which claims priority from U.S. patent application 60/240,905filed Dec. 29, 1999, the entire disclosure of both being herebyincorporated by reference.

In accordance with this invention a process for the production of6,7,8-substituted 3-amino-2-naphthoates or 3-amino-2-naphthonitriles (A)in high purity and as single regioisomers is provided by a process whichcomprises:

-   (a) Preparation of alpha-substituted 1-cyanobenzocyclobutenes 2 by    reacting the anions of the 1-cyanobenzocyclobutenes 1 with an    appropriate electrophile, preferably a diphenyl disulfide or a    substituted diphenyl disulfide.-   (b) Reaction of an anionic salt of an ester or acetonitrile with the    above cyanobenzocyclobutenes 2 to provide amino ester or amino    nitrile intermediates 3.-   (c) Thermal cyclization of the amino ester or amino nitrile    intermediates 3 to provide 6,7,8-substituted 3-amino-2-naphthoates    or 6,7,8-substituted 3-amino-2-naphthonitriles (A).

Literature methods exist for construction of the starting materialbenzocyclobutenes 1 in regioisomerically pure form: e.g., Kametani, T.et al J. Het. Chem, 11, 179, (1974), Kametani, T.; kondoh, H.; Tsubuki,M.; Honda, T. J. Chem. Soc Perkin Trans. 1, 5 (1990), Kametani, T.;Kato, Honda, T. Fukumoto, K. J. Chem. Soc Perkin 1, 2001 (1990),Kametani, T.; Kajiwara, M.; Takahashi, T.; Fukumoto, K. Tetrahedron, 31,949 (1975) and Honda, T. Toya, T. Heterocycles, 33, 291 (1992), in whichR₁, R₂ and R₃ are alkoxy of 1 to 4 carbon atoms, benzyloxy or alkyl of 1to 6 carbon atoms. The chemistry outlined in scheme 1 represents a novelreaction sequence which provides 6,7,8-substituted 3-amino-2-naphthoatesor 6,7,8-substituted 3-amino-2-naphthonitriles (A) as singleregioisomers.

The reaction of the substitutedbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitriles 1 with a base,preferably a strong base such as sodium (bistrimethylsilyl)amide orn-butyllithium at a temperature of about 0° to about −100° C.,preferably about −30° to about −78° C. provides the corresponding aniona to the cyano group which is then reacted with a suitable electrophileR₁₀—S-L′ where L′ is any conventional leaving group, including halogen,alkylthio, phenylthio, benzylthio, heteroarylthio,alkylmethanesulfonate, phenylsulfonate, benzylsulfonate,heteroarylsulfonate, alkylsulfoxide, phenylsulfoxide, benzylsulfoxide,heteroarylsulfoxide, dialkyl amine, or heterocyclic amine such asmorpholine, R₁₀ is an alkyl of 1-10 carbons, cycloalkyl of 3-10 carbons,alkenyl of 3-10 carbons, cycloalkenyl of 4-10 carbons, alkynyl of 3-10carbons, Ph or L (where Ph and L are as hereinabove defined), the alkyl,cycloalkyl, alkenyl, cycloalkenyl and alkynyl groups may be optionallysubstituted with one or more Ph or L groups, a disulfide being preferredand the di-p-chlorophenyl disulfide being especially preferred, andallow the reaction to warm up to about room temperature to providesubstituted7-phenylsulfanylbicyclo[4.2.0]octa-1,3,5-triene-7-carbonitriles 2.Reaction of these intermediates with an acetonitrile or ester anion suchas but not limited to zinc exchange from a alkyl bromoacetate orpreferably a magnesium bromide salt of acetonitrile or an alkyl estersuch as, but not limited to t-butyl acetate in an inert solvent such asether or tetrahydrofuran and the like provides the correspondingsubstituted esters or nitriles 3. Refluxing these adducts in a solvent,preferably a solvent with a boiling point in the range of about 140° toabout 200° C. such as dichlorobenzene or the like provides thesubstituted esters or nitriles A. Preferably refluxing the adducts willtake less than 5 hours and more preferably from about 0.5 to 3 hours. IfR₁₀ is Ph or L or R₁₀ has an alkyl, cycloalkyl, alkenyl, cycloalkenyl,or alkynyl group substituted with Ph or L, the preferred Ph and Lmoieties for such R₁₀ are a phenyl or heteroaryl group optionallysubstituted with halogen, alkyl of 1-6 carbons, alkoxy of 1-6 carbons,alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms,trifluoromethyl, cyano, or nitro.

Compounds A can be converted to the desiredbenzo[g]quinoline-3-carbonitriles of Formula B, which possess potentactivity as protein kinase inhibitors, by the chemistry shown in scheme2 and described below.

Reaction of 3-amino-2-naphthoic esters (A) with dimethylformamidedialkyl acetal such as dimethylformamide dimethyl acetal, with orwithout a solvent such as toluene, gives the corresponding amidineintermediates. The reaction of the amidine intermediates with thelithium anion of acetonitrile prepared by using a base such asn-butyllithium or the like in an inert solvent gives3-cyano-4-oxo-1,4-dihydrobenzo[g]quinolines 4 or the3-cyano-4-hydroxybenzo[g]quinoline tautomers thereof. Heating 4, with orwithout solvent, with a halogenating agent preferably a chlorinatingagent such as phosphorus oxychloride or oxalyl chloride provides thecorresponding 4-chloro-3-cyanobenzo[g]quinolines 5. Condensation of4-chloro-3-cyanobenzo[g]quinolines 5 with a nucleophilic amine, aniline,mercaptan, thiophenol, phenol, or alcohol reagent of Formula 6,HX—(CH₂)_(n)—Ar, wherein Ar, X and n are as hereinbefore defined, givethe benzo[g]quinoline-3-carbonitriles of Formula B. The condensation canbe carried out at room temperature, but can be accelerated by heatingthe reaction mixture, preferably to about 800 to 140° C., together withone equivalent of pyridine hydrochloride or by using bases such astrialkylamines, or sodium hydride in an inert solvent, sodium orpotassium alkoxides in an alcohol solvent, or by using transition metalcatalysts such as tris(dibenzylideneacetone)dipalladium(0) or the like,together with ligands such as, but not limited to2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, and potassiumphosphate in an inert solvent.

It will be recognized by those skilled in the art that the3-cyano-4-hydroxybenzo[g]quinoline tautomer may be converted to leavinggroups such as halogen, tosyl, mesyl, aryl- or alkyl-sulfonate,preferably trifluoromethanesulfonate and the like.

When the nucleophile 6 contains primary or secondary amino or hydroxylgroups, it may be necessary to protect these groups prior to thereaction with 4-chloro-3-cyanobenzo[g]quinoline 5. The same amine oralcohol protecting groups described herein below can be used and theycan be removed from the products of Formula B as described.

In addition, intermediates A can be converted to benzo[g]quinazolines C.The methodology outlined in Scheme 3 provides for the regioselectivesynthesis of substituted benzo[g]quinazolines with substituentsanalogous to those utilized in the case of thebenzo[g]quinoline-3-carbonitriles

Intermediates A can be converted to compounds 7 by refluxing informamide or the like for about 1-5 hours. Heating 7, with or withoutsolvent such as toluene, with a halogenating agent, preferably achlorinating agent such as phosphorus oxychloride or oxalyl chloride,with or without a base such as diethylaniline, provides thecorresponding 4-chlorobenzo[g]quinazolines 8. Condensation of4-chlorobenzo[g]quinazolines 8 with a nucleophilic amine, aniline,mercaptan, thiophenol, phenol, or alcohol reagent of Formula 6,HX—(CH₂)_(n)—Ar, wherein Ar, X and n are as hereinbefore defined, givethe benzo[g]quinazolines of Formula C. The condensation can be carriedout at room temperature or can be accelerated by: heating the reactionmixture together with one equivalent of pyridine hydrochloride; or byusing bases such as trialkylamines, sodium hydride in an inert solvent,sodium or potassium alkoxides in an alcohol solvent; or by usingtransition metal catalysts such astris(dibenzylideneacetone)dipalladium(0) or the like, together withligands such as, but not limited to2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, and potassiumphosphate or the like in an inert solvent.

When the nucleophile 6 contains primary or secondary amino or hydroxylgroups, it may be necessary to protect these groups prior to thereaction with 4-chloroquinazoline 8. The same amine or alcoholprotecting groups described herein below can be used and they can beremoved from the products of Formula C as described.

An alternative method to provide 4-anilino-benzo[g]quinazolines is shownin scheme 4.

Reaction of intermediates A with, for example, dimethylformamidedimethyl acetal, with or without a solvent, gives the correspondingamidine intermediates 9. Heating the amidine intermediates 9 with anappropriately substituted amine 6 in acetic acid, preferably from 50° to115° C. from 0.5 to 24 hours, provides the products of Formula C.

Converting the R₁, R₂ and R₃ groups to those hereinabove described canbe accomplished through any conventionally known techniques, forexample:

Where one or more of R₁, R₂, and R₃ of 1, 2, 3, 4, 6, 7, 8, 9 or FormulaA, B, or C is a methoxy group, it can be converted to the correspondinghydroxy group by reaction with a demethylating agent such as borontribromide in an inert solvent or by heating with pyridinium chloridewith or without solvent;

where one or more of R₁, R₂, and R₃ of 1, 2, 3, 4, 5, 7, 8, 9 or FormulaA, B, or C is a benzyloxy group, it can be converted to thecorresponding hydroxy group by reaction with a debenzylating agent suchas boron tribromide in an inert solvent, hydrochloric acid,trifluoroacetic acid or catalytic hydrogenation with a catalyst such aspalladium-on-carbon;

where one or more of R₁, R₂, and R₃ of 1, 2, 3, 4, 5, 7, 8, 9 or FormulaA, B, or C is a hydroxy group, it can be converted to a substitutedalkoxy by reacting with an appropriately substituted alcohol usingtriphenyl phosphine and diethyl azodicarboxylate in an inert solvent, oralternatively by first reacting with a reagent such as, but not limitedto, a bromoalkyl chloride or chloroalkyl tosylate to provide anIntermediate which can be converted to the above described groups bysubsequent reaction with an appropriately substituted nucleophile.

where one or more of R₁, R₂, and R₃ of 1, 2, 3, 4, 5, 7, 8, 9 or FormulaA, B, or C is a hydroxy group, it can be converted to a substitutedbenzyloxy, substituted phenoxy or cycloalkoxy by reacting with anappropriately substituted alcohol using triphenyl phosphine and diethylazodicarboxylate in an inert solvent.

where one or more of R₁, R₂, and R₃ of 1, 2, 3, 4, 5, 7, 8, 9 or FormulaA, B, or C is a hydroxy group, it can be converted to atrifluoromethanesulfonate using trifluoromethanesulfonate anhydride orN-phenyltrifluoromethylsulfonamide and a base such as triethylamine inan inert solvent;

where one or more of R₁, R₂, and R₃ of 1, 2, 3, 4, 5, 7, 8, 9 or FormulaA, B, or C is a trifluoromethanesulfonate, it can be converted to analkylamino of 1-6 carbons, dialkylamino of 2-12 carbons, benzylamino,dibenzylamino, arylamino, arylalkylamino group by reaction with anappropriately substituted amine and a palladium catalyst such as, butnot limited to bis(dibenzylideneacetone)palladium, dichlorobis(tri-orthotolylphosphine) palladium and ligands such as2,2′-bis(diphenylphosphinyl)-1,1′-binaphthalene (BINAP), tri-t-butylphosphine or 1,1′-bis(di-tert-butylphosphino)ferrocene together with orwithout a base such as sodium t-butoxide in an inert solvent;

where one or more of R₁, R₂, and R₃ of 1, 2, 3, 4, 5, 7, 8, 9 or FormulaA, B, or C is a benzylamino or dibenzylamino group, it can be convertedto an amino group by catalytic hydrogenation with a catalyst such aspalladium-on-carbon, or sodium in ammonia.

In those cases where one or more of R₁, R₂, and R₃ of 1, 2, 3, 4, 5, 7,8, 9 or Formula A, B, or C may contain an asymmetric carbon atom, theintermediates can be used as the racemate or as the individual R or Senantiomers in which case the compounds of this invention will be in theracemic or R and S optically active forms, respectively. In cases wherethe substituents may contain more than one asymmetric carbon atom,diastereomers may be present; these can be separated by methods wellknown in the art including, but not limited to, fractionalcrystallization and chromatographic methods. When 1, 2, 3, 4, 6, 6, 7,8, 9 or Formula A, B, or C contains primary or secondary amino groups,it may be necessary to protect these groups prior to the next reaction.Suitable protecting groups include, but are not limited totert-butoxycarbonyl (BOC), beta-trimethylsilylethanesulfonamide (SES),benzyloxycarbonyl (CBZ) and benzyl (Bn) protecting groups. The firstprotecting group listed above can be removed from the final products bytreatment with an acid such as trifluoroactic acid, the secondprotecting group with a fluoride salt, such as cesium fluoride ortetrabutylammonium fluoride. The latter two protecting groups can beremoved by catalytic hydrogenation or sodium in ammonia. In those caseswhere 1, 2, 3, 4, 5, 6, 7, 8, 9 or Formula A, B, or C contains hydroxylgroups, the hydroxyl groups may first have to be protected prior to thesubsequent reaction. Suitable protecting groups include, but are notlimited to, t-butyidimethylsilyl, tetrahydropyranyl, or benzylprotecting groups. The first two protecting groups listed above can beremoved from the final products by treatment with an acid such as aceticacid or hydrochloric acid while the latter protecting group can beremoved by catalytic hydrogenation.

EXAMPLE 1 5-(Benzyloxy)-1-bromo-2-(bromomethyl)-4-methoxybenzene

4-Benzyloxy-3-methoxybenzyl alcohol (1 g, 4.1 mmol) is dissolved inacetic acid (3 ml) and cooled to 10° C. in a water/ice bath. A solutionof bromine (0.25 ml, 4.92 mmol) in acetic acid (0.25 ml) is addeddropwise to the reaction mixture while stirring. The reaction is allowedto warm to room temperature and is stirred for 18 hours. The reaction isdiluted with water and the resulting precipitate is collected byfiltration. The precipitate is washed well with water and recrystallizedfrom a small amount of methanol to yield 1.3 g of5-(benzyloxy)-1-bromo-2-(bromomethyl)-4-methoxybenzene as a white solid,mp 103-105° C.

¹HNMR (d⁶-DMSO): δ 7.5 (m, 7H); 5.09 (s, 2H); 4.69 (s, 2H); 3.77 (s, 3H)

MS (ES, positive ion mode): m/z calcd for C₁₅H₁₄Br₂O₂: 386.08, found(M+H)⁺ 387.1

Analysis for C₁₅H₁₄Br₂O₂.0.3CH₃OH Calcd: C, 47.60; H, 3.84. Found: C,47.44; H, 3.77.

EXAMPLE 2 3-(4-Benzyloxy-2-bromo-5-methoxyphenyl)-propionitrile

To a solution of n-butyllithium (1.8 mL of a 2.5 M solution in hexane,4.5 mmol) in 5 mL of tetrahydrofuran is added a solution of acetonitrile(1.0 mL, 19.1 mmol) in 5 mL of tetrahydrofuran. The reaction mixture isstirred at −78° C. for 15 min. A solution of5-(benzyloxy)-1-bromo-2-(bromomethyl)-4-methoxybenzene (0.7 g, 1.8 mmol)in 3 mL of tetrahydrofuran is added and stirring is continued for 1 hourat −78° C. The reaction is quenched by the addition of 15 mL of waterand the mixture is allowed to warm to room temperature. The mixture isextracted with ethyl acetate and the organic layers combined, then driedwith sodium sulfate. After reducing in vacuo, the crude product ispurified by flash chromatography using a gradient of 95:5 to 4:1hexanes/ethyl acetate as an eluent. The clean fractions are combined,reduced in vacuo and dried to yield 0.343 g of3-(4-benzyloxy-2-bromo-5-methoxyphenyl)-propionitrile as a white solid,mp 52-53° C.

¹HNMR (d⁶-DMSO): δ 7.39 (m, 5H); 7.33 (s, 1H); 7.08 (s, 1H); 5.09 (s,2H); 3.77 (s, 3H); 2.92 (t, 2H; J=5.49), 2.78 (t, 2H; J=5.07).

MS (ES, positive ion mode): m/z calcd for C₁₇H₁₈BrNO₂: 346.22, found(M+H)⁺ 347.1

Analysis for C₁₇H₁₆BrNO₂ Calcd: C, 58.98; H, 4.66; N, 4.05. Found: C,58.77; H, 4.71; N, 3.89.

EXAMPLE 34-Benzyloxy-3-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile

A suspension of sodium amide is prepared from 100 mL of liquid ammonia,sodium (0.52 g, 22.8 mmol) and a catalytic amount of ferric nitrate. Tothis is added 3-(4-benzyloxy-2-bromo-5-methoxyphenyl)-propionitrile (2g, 5.7 mmol) in portions and the reaction is stirred at −33° C. for 45minutes. The reaction is then cooled down to −78° C. and quenched withammonium chloride. The liquid ammonia is allowed to evaporate and theresulting solid residue is washed with water. The tan solid obtained ispurified by flash chromatography, using 4:1 hexanes/ethyl acetate as aneluent. The clean fractions are combined and reduced in vacuo to yield 1g of 4-benzyloxy-3-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrileas a clear oil that solidifies into a white solid upon standing, mp 85°C.

¹HNMR (d⁶-DMSO): δ 7.39 (m, 5H); 7.04 (s, 1H); 6.89 (s, 1H); 5.08 (d,1H, J=12.15); 5.05 (d. 1H, J=12.12); 4.45 (dd, 1H, J=1.74, 3.93), 3.74(s, 3H); 3.6 (dd, 1H, J=3.99, 10.29), 3.35 (d, 1H, J=1.77)

MS (ES, positive ion mode): m/z calcd for C₁₇H₁₅NO₂: 265.31, found(M+H)⁺ 266.1

Analysis for C₁₇H₁₅NO₂ Calcd: C, 76.96; H, 5.70; N, 5.28. Found: C,76.87; H, 5.97; N, 5.01.

EXAMPLE 44-Benzyloxy-7-(4-chloro-phenylsulfanyl)-3-methoxybicyclo[4.2.0]Octa-1,3,5-triene-7-carbonitrile

To a solution of4-benzyloxy-3-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile (1.0g, 3.7 mmol) in anhydrous tetrahydrofuran (10 mL) at −78° C. is addedsodium bis(trimethylsilyl) amide (5.65 mL of a 1M solution intetrahydrofuran, 5.6 mmol) over a period of 4 minutes, followed by theaddition of 4,4′-dichlorodiphenyl disulfide in one portion. The reactionis stirred at −78° C. for 15 minutes and then at room temperature forone hour. The reaction is then diluted and extracted with ethyl acetate.The organic layer is collected and dried with sodium sulfate. Afterreducing in vacuo, the crude material is purified by flashchromatography using 4:1 hexanes/ethyl acetate. The clean fractions arecombined, reduced and dried to yield 1.3 g of4-benzyloxy-7-(4-chloro-phenylsulfanyl)-3-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrileas an off-white solid, mp 114-115° C.

¹HNMR (d⁶-DMSO): δ 7.62-7.54 (m, 4H); 7.41 (m, 4H); 7.36 (m, 1H); 6.97(s, 1H); 6.83 (s, 1H); 5.08 (dd, 2H, J=9.07, 10.53); 3.98 (d, 1H,J=10.47), 3.78 (s, 3H); 3.60 (d, 1H, J=10.5)

MS (ES, positive ion mode): m/z calcd for C₂₃H₁₈ClNO₂S: 408.92, found(M+H)⁺ 408.1

Analysis for C₂₃H₁₈ClNO₂S Calcd: C, 67.72; H, 4.45; N, 3.43. Found: C,67.99; H, 4.63; N, 3.33.

EXAMPLE 54-Benzyloxy-3-methoxy-7-phenylsulfanylbicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile

To a solution of4-benzyloxy-3-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile(7.22 g, 3.7 mmol) in anhydrous tetrahydrofuran (60 mL) at −78° C. isadded sodium bis(trimethylsilyl)amide (41.0 mL of a 1M solution intetrahydrofuran, 41.0 mmol) over a period of 4 minutes, followed by theaddition of 11.9 g (54.5 mmol) of phenyl disulfide in one portion. Thereaction is stirred at −78° C. for 15 minutes and then at roomtemperature for one hour. The reaction is quenched with water andextracted with ethyl acetate. The organic layers are combined and driedwith sodium sulfate. After reducing in vacuo, the crude material ispurified by flash chromatography using 4:1 hexanes/ethyl acetate. Theclean fractions are combined, reduced and dried to yield 7.0 g of4-benzyloxy-3-methoxy-7-phenylsulfanylbicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrileas a white solid, mp 109-110° C.

¹HNMR (d⁶-DMSO): δ 7.60-7.52 (m, 2H); 7.51-7.48 (m, 3H); 7.42-7.34 (m,5H); 6.97 (s, 1H); 6.80 (s, 1H); 5.03 (dd, 2H, J=9.0 Hz, 11.4 Hz); 4.01(d, 1H, J=10.5 Hz); 3.78 (s, 3H); 3.60 (d, 1H, J=10.5)

MS (ES, positive ion mode): m/z calcd for C₂₃H₁₉NO₂S: 373.5, found(M+H)⁺ 374.0

Analysis for C₂₃H₁₉NO₂S Calcd: C, 73.97; H, 5.13; N, 3.75. Found: C,73.83; H, 5.16; N, 3.53.

EXAMPLE 63-Amino-3-[4-benzyloxy-7-(4-chloro-phenylsulfanyl)-3-methoxybicyclo[4.2]octa-1,3,5-trien-7-yl]-acrylicacid tert-butyl ester

To a stirred solution of ethylmagnesium bromide (3.26 mL of a 3Msolution in diethyl ether, 9.8 mmol) in anhydrous tetrahydrofuran (10mL) at 0° C. under nitrogen is added diisopropylamine (2.75 mL, 19.6mmol). The mixture is stirred at 0° C. for 1 hour. t-Butyl acetate (0.5mL, 3.6 mmol) and a solution of 1.0 g (2.45 mmol) of4-benzyloxy-7-(4-chloro-phenylsulfanyl)-3-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrilein anhydrous tetrahydrofuran (10 mL) are added successively, and theresulting mixture is stirred for an additional hour. The reaction isquenched with aqueous ammonium chloride and the product mixture isextracted with ethyl acetate. The ethyl acetate extract is washed withbrine, dried over anhydrous sodium sulfate and passed through a plug ofsilica to give3-amino-3-[4-benzyloxy-7-(4-chloro-phenylsulfanyl)-3-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-acrylicacid tert-butyl ester as a clear oil, that solidifies upon standing, mp112-115° C.

¹HNMR (d⁶-DMSO): δ 7.60-7.29 (m, 9H); 6.81 (s, 1H); 6.72 (s, 1H); 5.08(dd, 2H, J=9.09, 11.82 Hz); 4.15 (s, 1H); 3.73 (s, 3H); 3.48 (d, 1H,J=10.7 Hz); 3.30 (d, 1H, J=10.6 Hz); 1.36 (s, 9H)

MS (ES, positive ion mode): m/z calcd for C₂₈H₃₀ClNO₄S: 524.1, found(M+H)⁺ 523.9

Analysis for C₂₉H₃₀ClNO₄S Calcd: C, 66.46; H, 5.77; N, 2.67. Found: C,66.31; H, 5.91; N, 2.61.

EXAMPLE 7 3-Amino-6-benzyloxy-7-methoxynaphthalene-2-carboxylic acidtert-butyl ester

Nitrogen gas is bubbled through a solution of3-amino-3-[4-benzyloxy-7-(4-chloro-phenylsulfanyl)-3-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-acrylicacid tert-butyl ester (0.6 g, 1.1 mmol) in 1,2-dichlorobenzene (100 mL)for 1 hour and the reaction is heated to 179° C. After one hour thereaction is cooled and reduced in vacuo. The residue is washed withether, dissolved in methylene chloride and purified through a plug ofsilica eluting with methylene chloride. The filtrate is reduced anddried to afford 0.321 g of3-amino-6-benzyloxy-7-methoxynaphthalene-2-carboxylic acid tert-butylester as a yellow solid, mp 179-180° C.

¹HNMR (d⁶-DMSO): δ 8.18 (s, 1H); 7.4 (m, 5H); 7.18 (s, 1H); 7.01 (s,1H); 6.85 (s, 1H); 6.21 (s, 2H), 5.17 (s, 2H); 3.74 (s, 3H), 1.58 (s,9H)

MS (ES, positive ion mode): m/z calcd for C₂₃H₂₅NO₄: 379.45, found(M+H)⁺ 379.9

Analysis for C₂₃H₂₅NO₄.0.7 H₂O Calcd: C, 70.50; H, 6.08; N, 3.57. Found:C, 70.45; H, 6.24; N, 3.40.

EXAMPLE 88-Benzyloxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile

In a round bottom flask containing 10 mL of toluene is added3-amino-6-benzyloxy-7-methoxynaphthalene-2-carboxylic acid tert-butylester (3.0 g, 7.9 mmol) and dimethylformamide dimethyl acetal (5.4 mL,31.6 mmol) under a positive nitrogen flow. The mixture is stirred at120° C. for 1.5 hour, then is cooled to room temperature. The volatilesare removed under reduced pressure and the resulting residue is dried invacuo for 15 h to yield 3.0 g of6-benzyloxy-3-(dimethylamino-methyleneamino)-7-methoxy-naphthalene-2-carboxylicacid tert-butyl ester as a dark oil.

To a solution of n-butyllithium (7.68 mL of a 2.5 M solution in hexane,19.2 mmol) in 30 mL of tetrahydrofuran is added a solution ofacetonitrile (3.34 mL, 64.0 mmol) in 50 mL of tetrahydrofuran. Thereaction mixture is stirred at −78° C. for 15 min. A solution of6-benzyloxy-3-(dimethylamino-methyleneamino)-7-methoxy-naphthalene-2-carboxylicacid tert-butyl ester obtained in the previous step (2.8 g, 6.4 mmol) in30 mL of tetrahydrofuran is added and stirring is continued for 1 h at−78° C. The reaction is quenched by the addition of 10 mL of glacialacetic acid and the mixture is allowed to warm up to room temperature.The volatiles are removed under reduced pressure and the resultingresidue is washed with water, then ethyl acetate and is dried in avacuum oven to yield 1.9 g of8-benzyloxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrileas a yellow solid, mp>300° C.

¹HNMR (d⁶-DMSO+TFA): δ 8.71 (s, 1H); 8.63 (s, 1H); 7.93 (s, 1H); 7.61(s, 1H); 7.58 (s, 1H); 7.43 (m, 5H); 5.27 (s, 2H), 3.74 (s, 3H)

MS (ES, positive ion mode): m/z calcd for C₂₂H₁₅N₂O₂: 356.38, found(M+H)⁺ 357.1

Analysis for C₂₂H₁₅N₂O₂.0.2 H₂O Calcd: C, 73.45; H, 4.54; N, 7.77.Found: C, 73.49; H, 4.49; N, 7.65.

EXAMPLE 9 3-Amino-6-hydroxy-7-methoxy-naphthalene-2-carboxylic acidtert-butyl ester

A solution of 4.7 g (12.0 mmol) of3-amino-6-benzyloxy-7-methoxynaphthalene-2-carboxylic acid tert-butylester and 2.0 g of 10% Pd/C in 40 mL of DMF and 100 mL of methanol isshaken on Parr shaker at 40 psi for 18 hours. The hydrogenation isrepeated twice more to bring the reaction to completion. The catalyst isfiltered through a pad of Celite, is washed with methanol and solvent isevaporated to yield a residue which is dissolved in methylene chloride.This is then filtered through a short pad of Magnesol and is washed withmethylene chloride and ethyl acetate. The filtrate is evaporated toyield 3.4 g of 3-amino-6-hydroxy-7-methoxy-naphthalene-2-carboxylic acidtert-butyl ester as a yellow solid, mp 262-263° C.

¹HNMR (d⁶-DMSO): δ 9.61 (bs, 1H); 8.15 (s, 1H); 7.13 (s, 1H); 6.74 (d,2H, J=2.7); 6.12 (s, 2H); 3.82 (s, 3H), 1.58 (s, 9H)

MS (ES, positive ion mode): m/z calcd for C₁₆H₁₉NO₄: 289.33, found(M+H)⁺ 289.9

Analysis for C₁₆H₁₉NO₄.0.1CH₃CO₂C₂H₅ Calcd: C, 66.06; H, 6.69; N, 4.70.Found: C, 66.30; H, 6.96; N, 4.30.

EXAMPLE 103-Amino-7-methoxy-6-(2-morpholinyl-4-yl-ethoxy)-naphthalene-2-carboxylicacid tert-butyl ester

To a solution of 0.72 g (2.49 mmol) of3-amino-6-hydroxy-7-methoxy-naphthalene-2-carboxylic acid tert-butylester in 7.5 ml of tetrahydrofuran is added 0.46 mL (3.74 mmol) of4-(2-hydroxyethyl)morpholine, followed by the addition of 1.34 g (4.98mmol) of diphenyl-2-pyridylphosphine and 0.6 mL (3.87 mmol) of diethylazadicarboxylate. The resulting mixture is stirred at room temperaturefor 1.5 hours, quenched with water, diluted with ethyl acetate and thetwo layers are separated. The organic layer is extracted with 0.2Nhydrochloric acid. After neutralizing the aqueous layer with a saturatedsolution of sodium bicarbonate, it is extracted with ethyl acetate. Theethyl acetate extract is dried over anhydrous sodium sulfate, filteredand evaporated to yield a brown oil. The oil is purified by silica gelchromatography, utilizing a gradient of ethyl acetate/hexane (85:15 to100:0), to give 0.7 g of3-amino-7-methoxy-6-(2-morpholin-4-yl-ethoxy)-naphthalene-2-carboxylicacid tert-butyl ester as an orange solid, mp 125-127° C.

¹HNMR (CDCl₃): δ 8.24 (s, 1H); 7.00 (s, 1H); 6.81 (d, 2H, J=2.34 Hz);5.47 (bs, 2H); 4.26 (t, 2H, J=4.5 Hz); 3.92 (s, 3H); 3.75 (t, 4H, J=3.45Hz); 2.93 (t, 2H, J=4.5 Hz); 2.65 (bs, 4H); 1.63 (s, 9H).

MS (ES, positive ion mode): m/z calcd for C₂₂H₃₀N₂O₅: 402.4, found(M+H)⁺ 403.3

Analysis for C₂₂H₃₀N₂O₅ Calcd: C, 65.65; H, 7.51; N, 6.96. Found: C,65.65; H, 7.30; N, 6.98.

EXAMPLE 117-Methoxy-8-(2-morpholin-4-yl-ethoxy)-3H-benzo[g]quinazolin-4-one

A mixture of 3.5 g (8.6 mmol) of3-amino-7-methoxy-6-(2-morpholin-4-yl-ethoxy)-naphthalene-2-carboxylicacid tert-butyl ester and 60 ml of formamide is heated at 178° C. for 2hours, then cooled. To this is added 4:1 methylene chloride/methanol.The resulting solution is washed several times with brine, dried overanhydrous sodium sulfate and evaporated to yield an oil. The oil ispurified by silica gel chromatography, utilizing a gradient of 99:1 to88:12 methylene chloride/methanol to give sticky solid, which istriturated with ethyl acetate to yield 1.5 g of7-methoxy-8-(2-morpholin-4-yl-ethoxy)-3H-benzo[g]quinazolin-4-one as atan solid, mp 230-232° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 9.39 (s, 1H); 8.83 (s, 1H); 8.17(s, 1H); 7.80 (s, 1H); 7.77 (s, 1H); 4.63 (t, 2H, J=3.3 Hz,); 4.05 (d,2H, J=8.9 Hz); 3.99 (s, 3H); 3.76 (m, 4H); 3.66 (d, 2H, J=9.3 Hz); 3.34(m, 2H).

MS (ES, positive ion mode): m/z calcd for C₁₉H₂₁N₃O₄: 355.4, found(M+H)⁺ 355.9

Analysis for C₁₉H₂₁N₃O₄.0.2 CH₃CO₂C₂H₅ Calcd: C, 63.75; H, 6.11; N,11.27. Found: C, 64.13; H, 6.04; N, 10.93.

EXAMPLE 127-Methoxy-8-(2-morpholin-4-yl-ethoxy)-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile

A mixture of 0.69 g (1.7 mmol) of3-amino-7-methoxy-6-(2-morpholin-4-yl-ethoxy)-naphthalene-2-carboxylicacid tert-butyl ester and 2.4 mL of N,N-dimethylformamide dimethylacetal in 7.0 mL of toluene is heated under reflux for 1.5 hours. Thesolvent is evaporated and the residue is dried on high vacuum to yield3-(dimethylamino-methyleneamino)-7-methoxy-6-(2-morpholin-4-yl-ethoxy)naphthalene-2-carboxylicacid tert-butyl ester as purple white foam.

To 15 mL of tetrahydrofuran at −78° C. is added 2.6 mL of n-butyllithium(1.6M in hexane) and the reaction mixture is stirred for 5 minutes. Tothis is added 0.36 mL (6.8 mmol) of acetonitrile dropwise, followed bystirring for 15 minutes. Finally, a solution of3-(dimethylamino-methyleneamino)-7-methoxy-6-(2-morpholin-4-yl-ethoxy)naphthalene-2-carboxylicacid tert-butyl ester in 5 mL of tetrahydrofuran is added dropwise overa period of 15 minutes. The resulting mixture is stirred at −78° C. for1 hour, then at room temperature for 1 hour. After cooling again to −78°C., the reaction is quenched with 0.5 mL of glacial acetic acid, the dryice bath is removed and the resulting thick slurry is stirred for 1hour. The solid is collected by filtration, washed with ethyl acetateand dried. Purification is carried out by silica gel chromatography,utilizing a gradient of 95:5 to 89:11 of methylene chloride/methanol togive 0.38 g of7-methoxy-8-(2-morpholin-4-yl-ethoxy)-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrileas a yellow solid, mp 275° C. (dec).

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 8.74 (s, 1H); 8.69 (s, 1H); 8.00(s, 1H); 7.65 (s, 1H); 7.59 (s, 1H); 4.59 (t, 2H, J=3.3 Hz,); 4.05 (d,2H, J=9.2 Hz); 3.97 (s, 3H); 3.75 (m, 4H); 3.66 (d, 2H, J=9.3 Hz); 3.34(t, 2H, J=7.0 Hz).

MS (ES, positive ion mode): m/z calcd for C₂₁H₂₁N₃O₄: 379.4, found(M+H)⁺ 380.2

Analysis for C₂₁H₂₁N₃O₄.2.5H₂O Calcd: C, 60.71; H, 6.07; N, 10.12.Found: C, 60.93; H, 6.11; N, 9.76.

EXAMPLE 138-Hydroxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile

A solution of 3.6 g (7.3 mmol) of8-benzyloxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrileand 0.7 g of 10% Pd/C in 240 mL of dimethyl formamide is hydrogenated ina Parr shaker at 40 psi for 24 hours. The catalyst is filtered through apad of Celite, Is washed with dimethyl formamide and the solvent isreduced in vacuo to yield a solid. The crude product is suspended inether, collected by filtration, further washed with ether and dried toyield 3.0 g of8-hydroxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile asa yellow solid, mp>300° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 8.67 (s, 1H); 8.64 (s, 1H); 7.84(s, 1H); 7.57 (s, 1H); 7.29 (s, 1H); 3.98 (s, 3H).

MS (ES, positive ion mode): m/z calcd for C₁₅H₁₀N₂O₃: 266.3, found(M+H)⁺ 266.8

Analysis for C₁₅H₁₀N₂O₃. 1.0 (CH₃)₂NCHO.0.8 H₂O Calcd: C, 61.11; H,5.30; N, 11.88. Found: C, 61.08; H, 4.81; N, 11.82.

EXAMPLE 14 4-Chloro-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile

A mixture of 3.0 g (11.3 mmol) of8-hydroxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrileand 20.0 mL of phosphorus oxychloride is heated under reflux for 0.5hour, then is cooled to room temperature. Excess phosphorus oxychlorideis evaporated to yield a residue, to which toluene is added and theresulting solution is reduced in vacuo. Toluene is added and evaporatedtwice more. The resulting residue is cooled with ice bath, neutralizedwith cold saturated solution of sodium bicarbonate and stirred. Thesolid was collected by filtration, is washed with cold water and isdried to yield 2.83 g of4-chloro-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile as a yellowsolid. A sample of the material is purified by silica gelchromatography, eluting with 97:3 methylene chloride/methanol to yield ayellow solid, mp.>300° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 8.68 (s, 1H); 8.64 (s, 1H); 7.83(s, 1H); 7.58 (s, 1H); 7.27 (s, 1H); 3.96 (s, 3H).

MS (ES, positive ion mode): m/z calcd for C₁₅H₉ClN₂O₂: 284.7, found(M+H)⁺ 284.7

Analysis for C₁₅H₉ClN₂O₂.0.6H₂O Calcd: C, 61.11; H, 5.30; N, 11.88.Found: C, 61.08; H, 4.81; N, 11.82.

EXAMPLE 154-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile

A mixture of 1.0 g (3.53 mmol) of4-chloro-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.93 g(3.88 mmol) of 3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamineand 0.41 g (3.52 mmol) of pyridine hydrochloride in 20 mL of2-ethoxyethanol is heated at 120° C. for 2 hours, then cooled to roomtemperature. The product mixture is diluted with a saturated solution ofsodium carbonate, stirred for 15 minutes and the solid is collected byfiltration. The solid is washed with water and dried in vacuo. The crudeproduct is purified by silica gel chromatography, utilizing a 95:5 to9:1 gradient of methylene chloride/methanol to give 1.13 g of4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrileas a yellow solid, mp>300° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 9.22 (d, 2H, J=5.1); 8.28 (s,1H); 8.06 (d, 1H, J=1.5 Hz); 7.98 (d, 1H, J=1.5 Hz); 7.92 (d, 1H, J=1.6Hz); 7.58 (dd, 1H, J=1.7 Hz, J=8.07 Hz); 7.49 (s, 1H); 7.44 (s, 1H); (d,1H, J=6.4 Hz); 4.05 (s, 3H); 3.88 (s, 3H).

MS (ES, positive ion mode): m/z calcd for C₂₅H₁₈ClN₅O₂S: 487.9, found(M+H)⁺ 487.7

Analysis for C₂₅H₁₈ClN₅O₂S.0.3H₂O Calcd: C, 60.86; H, 3.80; N, 14.20.Found: C, 60.82; H, 3.66; N, 14.03.

EXAMPLE 168-(2-Chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxybenzo[g]quinoline-3-carbonitrile

A mixture of 0.8 g (1.64 mmol) of4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile,0.48 g (2.05 mmol) of 2-chloroethyl p-toluene sulfonate and 0.8 g (2.46mmol) of cesium carbonate in 15 mL of dry dimethyl formamide was heatedat 40° C. for 2 hours. To this was added 0.2 g (0.85 mmol) of2-chloroethyl p-toluene sulfonate and 0.4 g (1.22 mmol) of cesiumcarbonate and the reaction mixture was further heated for 2 hours. Aftercooling to room temperature, the mixture was poured on to ice. The solidwas collected by filtration, washed with water and ether, and dried toyield 1.0 g of dark yellow solid. A sample of the solid was purified bypreparatory thin layer chromatography, eluting with 95:5% methylenechloride/methanol to give8-(2-chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxybenzo[g]quinoline-3-carbonitrileas a yellow solid, mp. 275-280° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 9.25 (d, 2H, J=7.3 Hz); 8.41 (s,1H); 8.06 (d, 1H, J=1.5 Hz); 7.98 (d, 1H, J=1.5 Hz); 7.93 (d, 1H, J=1.7Hz); 7.78 (s, 1H); 7.58 (dd, 1H, J=1.7 Hz, 9.9 Hz); 7.45 (s, 1H); 7.33(d, 1H, J=6.4 Hz); 4.55 (t, 2H, J=3.6 Hz): 4.11 (t, 2H, J=3.9 Hz); 4.04(s, 3H); 3.85 (s, 3H).

MS (ES, positive ion mode): m/z calcd for C₂₇H₂₁Cl₂N₅O₂S: 550.5, found(M+H)⁺ 549.7

Analysis for C₂₇H₂₁Cl₂N₅O₂S.1.7 H₂O Calcd: C, 55.80; H, 4.23; N, 12.05.Found: C, 56.05; H, 4.14; N, 11.70.

EXAMPLE 174-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile

Procedure 1:

A mixture of 1.27 g (2.3 mmol) of8-(2-chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxybenzo[g]quinoline-3-carbonitrile,4.0 mL of morpholine and 0.1 g of sodium iodide in 10 mL of1,2-dimethoxyethane is heated under reflux for 16 hours. After allowingthe reaction to cool, the solvent is evaporated to yield a residue,which is stirred with saturated sodium bicarbonate. The solid iscollected by filtration, is washed with water and dried. The crudeproduct is purified by silica gel chromatography, utilizing a gradientof 98:2 to 90:10 of methylene chloride/methanol to give 0.53 g of4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrileas a yellow solid, mp>300° C.

Procedure 2:

4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile

A mixture of 2.32 g (6.11 mmol) of7-methoxy-8-(2-morpholin-4-yl-ethoxy)-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrileand 35 mL of phosphorus oxychloride is heated under reflux for 1 hour,then cooled to room temperature. Excess phosphorus oxychloride isevaporated to yield a residue, to which toluene is added and theresulting solution is reduced in vacuo. Toluene is added and evaporatedtwice more. The resulting residue is cooled with ice bath, neutralizedwith cold saturated solution of sodium bicarbonate and stirred. Thesolid is collected by filtration, is washed with cold water and dried toyield 1.989 g of4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrileas a yellow solid.

MS (ES, positive ion mode): m/z calcd for C₂₁H₂₀ClN₃O₄397.9, found(M+H)⁺ 398.2

A mixture of 1.98 g (4.98 mmol) of4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile,1.31 g (5.47 mmol) of3-chloro-4(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamine and 0.6 g (5.2mmol) of pyridine hydrochloride in 2-ethoxyethanol is heated at 120° C.for 1.25 hours, then cooled. The crude mixture is poured into a solutionof saturated sodium bicarbonate/ice and stirred for 45 minutes. Theresulting solid is collected by filtration, then washed with water,ether and ethyl acetate successively. After drying in vacuo, the solidis purified by silica gel chromatography, using a 94:6 to 9:1 gradientof methylene chloride/methanol to provide a yellow solid. This solid issuspended in ether, filtered, and further washed with ether. Afterdrying in vacuo, 1.77 g of4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrileis obtained as a yellow solid, mp.>300° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 9.28 (s, 2H,); 8.45 (s, 1H);8.06 (d, 1H, J=1.5 Hz); 7.98 (d, 1H, J=1.5 Hz); 7.93 (d, 1H, J=1.7 Hz);7.83 (s, 1H); 7.58 (dd, 1H, J=1.7 Hz, 6.4 Hz); 7.48 (s, 1H); 7.35 (d,1H, J=6.4 Hz); 4.67 (t, 2H, J=3.6 Hz); 4.06 (m, 2H); 4.04 (s, 3H); 3.87(s, 3H); 3.77 (m, 4H); 3.67 (d, 2H, J=9.3 Hz); 3.36 (t, 2H, J=3.6 Hz).

MS (ES, positive ion mode): m/z calcd for C₃₁H₂₉ClN₆O₃S: 601.1, found(M+H)⁺ 601.2

Analysis for C₃₁H₂₉ClN₆O₃S.1.7 H₂O Calcd: C, 55.80; H, 4.23; N, 12.05.Found: C, 56.05; H, 4.14; N, 11.70.

EXAMPLE 184-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-(3-chloropropoxy)-7-methoxybenzo[g]quinoline-3-carbonitrile

Following the procedure of Example 16, 0.3 g (0.61 mmol) of4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrileis reacted with 0.19 g (0.77 mmol) of 3-chloropropyl p-toluene sulfonateand 0.3 g of (0.92 mmol) of cesium carbonate, then an additional 0.05 g(0.2 mmol) of 3-chloropropyl p-toluene sulfonate and 0.07 g (0.2 mmol)of cesium carbonate in 5 mL of dry dimethyl formamide to provide 0.3 gof a beige solid. A sample of the solid is purified by silica gelchromatography, utilizing a 99:1 to 95:5 gradient of methylenechloride/methanol to give4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-(3-chloropropoxy)-7-methoxybenzo[g]quinoline-3-carbonitrileas an orange solid, mp>300° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 9.25 (d, 2H, J=8.6 Hz); 8.42 (s,1H); 8.06 (d, 1H, J=1.5 Hz); 7.98 (d, 1H, J=1.5 Hz); 7.93 (d, 1H, J=1.7Hz); 7.78 (s, 1H); 7.57 (dd, 1H, J=1.7 Hz, 6.4 Hz); 7.44 (s, 1H); 7.33(d, 1H, J=6.4); 4.39 (t, 2H, J=4.5 Hz); 4.03 (s, 3H); 3.87 (m, 2H); 3.86(s, 3H); 2.35 (m, 2H).

MS (ES, positive ion mode): m/z calcd for C₂₈H₂₃Cl₂N₅O₂S: 564.5, found(M+H)⁺ 563.6

Analysis for C₂₈H₂₃Cl₂N₅O₂S.2.0 H₂O Calcd: C, 56.51; H, 4.53; N, 11.66.Found: C, 56.51; H, 4.04; N, 11.37.

EXAMPLE 194-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-(3-morpholin-4-yl-propoxy)benzo[g]quinoline-3-carbonitrile

Following procedure 1 of Example 17, a mixture of 0.13 g (0.22 mmol) of4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-(3-chloropropoxy)-7-methoxybenzo[g]quinoline-3-carbonitrile,0.3 mL of morpholine and 0.01 g of sodium iodide is heated under refluxfor 16 hours, to provide 0.054 g of a yellow solid. A sample of thesolid is purified by silica gel chromatography, utilizing a 97:3 to90:10 gradient of methylene chloride/methanol to give4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-(3-morpholin-4-yl-propoxy)benzo[g]quinoline-3-carbonitrileas a yellow solid, mp 230-235° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 9.26 (s, 2H,); 8.42 (s, 1H);8.05 (d, 1H, J=1.2 Hz); 7.97 (d, 1H, J=1.2 Hz); 7.92 (d, 1H, J=1.6 Hz);7.73 (s, 1H); 7.57 (dd, 1H, J=1.6 Hz, 6.3 Hz); 7.46 (s, 1H); 7.33 (d,1H, J=6.4 Hz); 4.36 (t, 2H, J=3.6 Hz); 4.07 (m, 2H); 4.02 (s, 3H); 3.85(s, 3H); 3.71 (t, 2H, J=9.1 Hz); 3.58 (d, 2H, J=9.1 Hz); 3.38 (t, 2H,J=5.4 Hz); 3.19 (t, 2H, J=8.0 Hz); 2.33 (m, 2H).

MS (ES, positive ion mode): m/z calcd for C₃₂H₃₁ClN₆O₃S: 615.2, found(M+H)⁺ 614.7

Analysis for C₃₂H₃₁ClN₆O₃S.1.5 H₂O Calcd: C, 59.85; H, 5.34; N, 13.09.Found: C, 59.78; H, 5.04; N, 12.98.

EXAMPLE 204-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-[2-(4-methylpiperazin-1-yl)ethoxy]-benzo[g]quinoline-3-carbonitrile

Following procedure 1 of Example 17, a mixture of 0.15 g (0.3 mmol) of8-(2-chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-Imidazol-2-ylsulfanyl)phenylamino]-7-methoxybenzo[g]quinoline-3-carbonitrile,0.5 mL of 1-methylpiperazine and 0.02 g of sodium iodide is heated underreflux for 16 hours. Purification of the material is carried out bysilica gel flash chromatography, utilizing a 90:10 to 85:15 gradient ofmethylene chloride/methanol to give 0.052 g of4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-[2-(4-methylpiperazin-1-yl)ethoxy]-benzo[g]quinoline-3-carbonitrileas a yellow solid, mp 184-186° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 9.28 (d, 2H, J=1.9 Hz); 8.45 (s,1H); 8.06 (d, 1H, J=1.4 Hz); 7.8 (d, 1H, J=1.4 Hz); 7.93 (d, 1H, J=1.7Hz); 7.82 (s, 1H); 7.57 (dd, 1H, J=1.7 Hz, 6.4 Hz); 7.49 (s, 1H); 7.34(d, 1H, J=6.4 Hz); 4.67 (m, 2H); 4.03 (s, 3H); 3.89 (m, 2H); 3.86 (s,3H); 3.71-3.25 (m, 6H); 3.2 (m, 2H); 2.97 (s, 3H).

MS (ES, positive ion mode): m/z calcd for C₃₂H₃₂ClN₇O₂S: 614.2, found(M+2H)²⁺ 307.6

Analysis for C₃₂H₃₂ClN₇O₂S.3.5 H₂O Calcd: C, 56.74; H, 5.80; N, 14.48.Found: C, 56.57; H, 5.46; N, 14.12.

EXAMPLE 214-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-(2-[1,2,3]triazol-2-yl-ethoxy)benzo[g]quinoline-3-carbonitrileAnd EXAMPLE 224-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-(2-[1,2,3]triazol-1-yl-ethoxy)benzo[g]quinoline-3-carbonitrile

A mixture of 0.3 g (0.55 mmol) of8-(2-chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxybenzo[g]quinoline-3-carbonitrile,0.32 mL (5.5 mmol) of 1H-1,2,3-triazole and 0.1 g (2.5 mmol) of sodiumhydroxide powder in 5 mL of N,N-dimethyl formamide is heated at 80° C.for 4.5 hours, then cooled and poured on to ice. The solid is collectedby filtration, washed with water and dried. The two isomers areseparated by silica gel chromatography, utilizing a 99:1 to 85:15gradient of ethyl acetate/methanol. The less polar material, 0.062 g of4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-(2-[1,2,3]triazol-2-yl-ethoxy)benzo[g]quinoline-3-carbonitrileis obtained as yellow solid, mp 235-237° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 9.22 (d, 2H, J=11.5 Hz); 8.4 (s,1H); 8.04 (d, 1H, J=1.4 Hz); 7.96 (d, 1H, J=1.4 Hz); 7.92 (d, 1H, J=1.7Hz); 7.81 (m, 3H); 7.55 (dd, 1H, J=1.7 Hz, 6.4 Hz); 7.43 (s, 1H); 7.30(d, 1H, J=6.4 Hz); 4.98 (t, 2H, J=3.8 Hz); 4.79 (t, 2H, J=3.8 Hz); 3.96(s, 3H); 3.84 (s, 3H).

MS (ES, positive ion mode): m/z calcd for C₂₉H₂₃ClN₈O₂S: 583.1, found(M+H)⁺ 582.7

Analysis for C₂₉H₂₃ClN₈O₂S.1 H₂O Calcd: C, 57.94; H, 4.19; N, 18.64.Found: C, 57.73; H, 4.10; N, 18.65.

The more polar material, 0.087 g of4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-(2-[1,2,3]triazol-1-yl-ethoxy)benzo[g]quinoline-3-carbonitrile,is obtained as an orange solid, mp 201-207° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 9.24 (d, 2H, J=8.9 Hz); 8.4 (s,1H); 8.24 (s, 1H); 8.06 (d, 1H, J=1.2 Hz); 7.98 (d, 1H, J=1.2 Hz); 7.93(d, 1H, J=1.5 Hz); 7.78 (d, 2H, J=5.1 Hz); 7.57 (dd, 1H, J=1.5 Hz, 6.3Hz); 7.43 (s, 1H); 7.33 (d, 1H, J=6.4 Hz); 4.99 (t, 2H, J=4.0 Hz); 4.71(t, 2H, J=3.6 Hz); 4.00 (s, 3H); 3.86 (s, 3H).

MS (ES, positive ion mode): m/z calcd for C₂₉H₂₃ClN₈O₂S: 583.1, found(M+H)⁺ 582.7

Analysis for C₂₉H₂₃ClN₈O₂S.2 H₂O Calcd: C, 56.26; H, 4.40; N, 18.10.Found: C, 56.34; H, 4.19; N, 17.83.

EXAMPLE 234-(2,4-Dichloro-5-methoxyphenylamino)-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile

A mixture of 0.7 g (2.46 mmol) of4-chloro-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.57 g(2.95 mmol) of 2,4-dichloro-5-methoxyaniline and 0.28 g (2.46 mmol) ofpyridine hydrochloride in 7 mL of 2-ethoxyethanol is heated at 120° C.for 2 hours, then cooled to room temperature. The product mixture isdiluted with saturated solution of sodium bicarbonate and stirred for 15minutes. The resulting solid is collected by filtration, washed withwater and dried. The crude product is purified by silica gelchromatography, utilizing a 98:2 to 90:10 gradient of methylenechloride/methanol to give 0.71 g of4-(2,4-dichloro-5-methoxyphenylamino)-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrileas a yellow solid, mp, 238-240° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 9.31 (s, 1H); 9.22 (s, 1H); 8.28(s, 1H); 7.89 (s, 1H); 7.64 (s, 1H); 7.44 (s, 1H); 7.41 (s, 1H); 4.03(s, 3H); 3.91 (s, 3H);

MS (ES, positive ion mode): m/z calcd for C₂₂H₁₅Cl₂N₃O₃: 440.3, found(M+H)⁺ 439.7

Analysis for C₂₂H₁₅Cl₂N₃O₃.1.0 H₂O Calcd: C, 57.65; H, 3.74; N, 9.17.Found: C, 57.80; H, 3.94; N, 8.82.

EXAMPLE 248-(3-Chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[g]quinoline-3-carbonitrile

Following the procedure of Example 16, 0.43 g (0.98 mmol) of4-(2,4-dichloro-5-methoxyphenylamino)-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrileis reacted with 0.31 g (1.25 mmol) of 3-chloropropyl p-toluene sulfonateand 0.48 g of (1.47 mmol) of cesium carbonate, then an additional 0.05 g(0.2 mmol) of 3-chloropropyl p-toluene sulfonate and 0.07 g (0.2 mmol)of cesium carbonate in 6 mL of dry dimethyl formamide. The crude productis purified by silica gel flash chromatography, utilizing a 99.5:0.5 to99:1 gradient of methylene chloride/methanol to give 0.118 g of8-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[g]quinoline-3-carbonitrileas a yellow solid, mp 220-223° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 9.35 (s, 1H); 9.25 (s, 1H); 8.44(s, 1H); 7.87 (s, 1H); 7.77 (s, 1H); 7.61 (s, 1H); 7.47 (s, 1H); 4.41(t, 2H, J=4.5 Hz); 4.06 (s, 3H); 3.93 (s, 3H); 3.88 (t, 2H, J=4.8 Hz);2.35 (m, 2H).

MS (ES, positive ion mode): m/z calcd for C₂₅H₂₀Cl₃N₃O₃: 516.8, found(M+H)⁺ 517.6

Analysis for C₂₅H₂₀Cl₃N₃O₃.0.5 H₂O Calcd: C, 57.10; H, 4.03; N, 7.99.Found: C, 57.01; H, 4.00; N, 7.86.

EXAMPLE 254-(2,4-Dichloro-5-methoxyphenylamino)-7-methoxy-8-(3-morpholin-4-yl-propoxy)benzo[g]quinoline-3-carbonitrile

Following procedure 1 of Example 17, a mixture of 0.105 g (0.20 mmol) of8-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[g]quinoline-3-carbonitrile,0.3 mL of morpholine and 0.01 g of sodium iodide in 10 mL of1,2-dimethoxyethane is heated under reflux for 7 hours. The resultingsolid is purified by silica gel chromatography, utilizing a 98:2 to 94:6gradient of methylene chloride/methanol to give 0.089 g of4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxy-8-(3-morpholin-4-yl-propoxy)benzo[g]quinoline-3-carbonitrileas a yellow solid, mp 205-208° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 9.37 (s, 1H); 9.26 (s, 1H); 8.44(s, 1H); 7.88 (s, 1H); 7.73 (s, 1H); 7.63 (s, 1H); 7.49 (s, 1H); 4.39(t, 2H, J=5.5 Hz); 4.09 (m, 2H); 4.05 (s, 3H); 3.93 (s, 3H); 3.75 (t,2H, J=11.7 Hz); 3.60 (d, 2H, J=12.2 Hz); 3.42 (t, 2H, J=7.0 Hz); 3.21(t, 2H, J=9.3 Hz); 2.35 (m, 2H).

MS (ES, positive ion mode): m/z calcd for C₂₉H₂₈Cl₂N₄O₄: 567.5, found(M+H)⁺ 566.7

Analysis for C₂₉H₂₈Cl₂N₄O₄.1.7 H₂O Calcd: C, 58.23; H, 5.29; N, 9.37.Found: C, 57.91; H, 5.15; N, 9.12.

EXAMPLE 264-(2,4-Dichloro-5-methoxyphenylamino)-7-methoxy-8-(2-[1,2,3]triazol-2-yl-ethoxy)benzo[g]quinoline-3-carbonitrileAnd EXAMPLE 274-(2,4-Dichloro-5-methoxyphenylamino)-7-methoxy-8-(2-[1,2,3]triazol-1-yl-ethoxy)benzo[g]quinoline-3-carbonitrile

Following the procedure of Example 16, 0.28 g (0.64 mmol) of4-(2,4-dichloro-5-methoxyphenylamino)-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrileis reacted with 0.18 g (0.76 mmol) of 2-chloroethyl p-toluene sulfonateand 0.3 g of (0.92 mmol) of cesium carbonate, then an additional 0.05 g(0.2 mmol) of 2-chloroethyl p-toluene sulfonate and 0.07 g (0.2 mmol) ofcesium carbonate in 5 mL of dry dimethyl formamide. This provides 0.31 gof8-(2-chloroethoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[g]quinoline-3-carbonitrileas a brown solid.

MS (ES, positive ion mode): m/z calcd for C₂₈H₂₃Cl₂N₅O₂S: 502.8, found(M+H)⁺ 503.7

A mixture of 0.31 g (0.62 mmol) of8-(2-chloroethoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[g]quinoline-3-carbonitrile,0.36 mL (6.1 mmol) of 1H-1,2,3-triazole and 0.11 g (2.8 mmol) of sodiumhydroxide powder in 5 mL of N,N-dimethyl formamide is heated at 80° C.for 4.5 hours, then cooled and poured on to ice. The solid is collectedby filtration, washed with water and dried. The two isomers areseparated by silica gel flash chromatography, using first 7:3 ethylacetate/hexane, then a 100:0 to 9:1 gradient of ethyl acetate/methanol.The less polar material, 0.071 g of4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxy-8-(2-[1,2,3]triazol-2-yl-ethoxy)benzo[g]quinoline-3-carbonitrile,is obtained as yellow solid, mp 285-287° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 9.34 (s, 1H); 9.22 (s, 1H); 8.44(s, 1H); 7.84 (s, 1H); 7.79 (s, 2H); 7.77 (s, 1H); 7.60 (s, 1H); 7.46(s, 1H); 5.01 (t, 2H, J=3.8 Hz); 4.84 (t, 2H, J=3.7 Hz); 4.00 (s, 3H);3.94 (s, 3H).

MS (ES, positive ion mode): m/z calcd for C₂₆H₂₀Cl₂N₆O₃: 535.4, found(M+H)⁺ 534.6

Analysis for C₂₆H₂₀Cl₂N₆O₃.0.5 H₂O Calcd: C, 57.36; H, 3.89; N, 15.44.Found: C, 57.45; H, 3.86; N, 15.14.

The more polar material, 0.053 g of4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxy-8-(2-[1,2,3]triazol-1-yl-ethoxy)benzo[g]quinoline-3-carbonitrile,is obtained as brown solid, mp 245° C. (dec).

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 9.35 (s, 1H); 9.27 (s, ₁H); 8.42(s, 1H); 8.25 (d, 1H, J=0.6 Hz); 7.89 (s, 1H); 7.79 (d, 2H, J=3.3 Hz);7.64 (s, 1H); 7.44 (s, 1H); 5.0 (t, 2H, J=3.8 Hz); 4.72 (t, 2H, J=3.7Hz); 4.03 (s, 3H); 3.91 (s, 3H).

MS (ES, positive ion mode): m/z calcd for C₂₈H₂₀Cl₂N₆O₃: 535.4, found(M+H)⁺ 534.6

Analysis for C₂₆H₂₀Cl₂N₆O₃.1.3H₂O Calcd: C, 55.88; H, 4.08; N, 15.04.Found: C, 55.97; H, 4.05; N, 14.86.

EXAMPLE 283-Amino-3-(4-benzyloxy-3-methoxy-7-phenylsulfanylbicyclo[4.2.0]octa-1,3,5-trien-7-yl)acrylonitrile

To a stirred solution of ethylmagnesium bromide (3.0 mL of a 3M solutionin diethyl ether, 9.0 mmol) in anhydrous tetrahydrofuran (10 mL) at 0°C. under nitrogen is added diisopropylamine (2.5 mL, 17.8 mmol). Themixture is stirred at 0° C. for 1 hour and acetonitrile (0.25 mL, 4.8mmol) and a solution of4-benzyloxy-3-methoxy-7-phenylsulfanylbicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile(0.83 g, 2.2 mmol) in anhydrous tetrahydrofuran (3 mL) are addedsuccessively, and the resulting mixture is stirred for an additionalhour. The reaction is quenched with aqueous ammonium chloride and theproduct is extracted with ethyl acetate. The extract is washed withbrine, dried over anhydrous sodium sulfate and evaporated to yield asolid. The crude product is purified by silica gel chromatography,utilizing a 9:1 to 4:1 gradient of hexane/ethyl acetate to yield 0.527 gof3-amino-3-(4-benzyloxy-3-methoxy-7-phenylsulfanylbicyclo[4.2.0]octa-1,3,5-trien-7-yl)acrylonitrileas a white solid, mp 122-125° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 7.43-7.37 (m, 5H); 7.35-7.31 (m,5H); 6.81 (s, 1H); 6.64 (s, 2H); 6.61 (s, 1H); 5.00 (d, 1H, J=12.1 Hz);4.94 (d, 1H, J=12.1 Hz); 3.72 (s, 3H); 3.57 (s, 1H); 3.49 (d, 1H, J=14.0Hz); 3.29 (d, 1H, J=13.0 Hz).

MS (ES, positive ion mode): m/z calcd for C₂₅H₂₂N₂O₂S: 414.5, found(M+H)⁺ 414.8

Analysis for C₂₅H₂₂N₂O₂S.0.3 H₂O Calcd: C, 71.50; H, 5.42; N, 6.67.Found: C, 71.51; H, 5.28; N, 6.56.

EXAMPLE 29 3-Amino-6-benzyloxy-7-methoxynaphthalene-2-carbonitrile

Nitrogen gas is bubbled through a solution of3-amino-3-(4-benzyloxy-3-methoxy-7-phenylsulfanylbicyclo[4.2.0]octa-1,3,5-trien-7-yl)acrylonitrile(0.39 g, 0.93 mmol) in 1,2-dichlorobenzene (500 mL) for 1 hour and thereaction is heated to 179° C. After 2.5 hours the reaction was cooleddown and reduced in vacuo. The residue was washed with ether, dissolvedin methylene chloride and purified through a plug of silica. Thefiltrate is reduced and dried to afford 0.19 g of3-amino-6-benzyloxy-7-methoxynaphthalene-2-carbonitrile as a yellowsolid, mp 241-243° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 7.98 (s, 1H); 7.61-7.44 (m, 2H);7.40-7.34 (m, 3H); 7.17 (s, 1H); 7.11 (s, 1H); 6.94 (s, 1H); 5.64 (s,2H), 5.19 (s, 2H); 3.81 (s, 3H).

MS (ES, positive ion mode): m/z calcd for C₁₉H₁₆N₂O₂: 304.3, found(M−H)+ 304.8

Analysis for C₁₉H₁₆N₂O₂.0.6 H₂O Calcd: C, 72.40; H, 5.50; N, 8.89.Found: C, 72.40; H, 5.34; N, 8.78.

EXAMPLE 30(8-Benzyloxy-7-methoxybenzo[g]quinazolin-4-yl)-(2,4-dichloro-5-methoxyphenyl)amine

A mixture of 0.12 g (1.7 mmol) of3-amino-6-benzyloxy-7-methoxynaphthalene-2-carbonitrile and 0.5 mL ofN,N-dimethylformamide dimethyl acetal in 2.0 mL of toluene is heatedunder reflux for 4 hours. The solvent is evaporated and the residue isdried on high vacuum to yieldN′-(7-benzyloxy-3-cyano-6-methoxynaphthalen-2-yl)-N,N-dimethylformamidineas an off-white solid.

A mixture ofN′-(7-benzyloxy-3-cyano-6-methoxynaphthalen-2-yl)-N,N-dimethylformamidineand 0.092 g (0.48 mmol) of 2,4-dichloro-5-methoxyaniline in 4 mL ofglacial acetic acid is heated under reflux for 7 hours, then cooled toroom temperature and stirred overnight. The resulting solid is collectedby filtration, washed with ether and dried to yield 0.05 g of(8-benzyloxy-7-methoxybenzo[g]quinazolin-4-yl)-(2,4-dichloro-5-methoxyphenyl)amineas a yellow solid, mp 275-280° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 9.25 (s, 1H); 8.95 (s, 1H); 8.28(s, 1H); 7.86 (s, 2H); 7.59-7.39 (m, 7H); 5.37 (s, 2H); 4.04 (s, 3H);3.90 (s, 3H).

MS (ES, positive ion mode): m/z calcd for C₂₇H₂₁Cl₂N₃O₃: 506.4, found(M−H)⁺ 505.7

Analysis for C₂₇H₂₁Cl₂N₃O₃.0.5 H₂O Calcd: C, 62.91; H, 4.30; N, 8.15.Found: C, 62.95; H, 4.45; N, 7.85.

EXAMPLE 314-Chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazoline

A mixture of 0.3 g (0.844 mmol) of7-methoxy-8-(2-morpholin-4-yl-ethoxy)-3H-benzo[g]quinazolin-4-one in 8mL of phosphorus oxychloride and 1 mL of diethylaniline is refluxed for15 minutes. After allowing to cool to room temperature, phosphorusoxychloride and diethylaniline are removed in vacuo. A 5 mL portion oftoluene is added to the crude product mixture, and the solvents areagain removed in vacuo. This step is repeated one more time. The productmixture is placed in an ice bath, and to this is added 10 mL of anice-cooled solution of saturated sodium bicarbonate. This is extractedtwice with a 95:5 mixture of methylene chloride/methanol, then with 1:1tetrahydrofuran/ethyl acetate. The organic layers are combined, driedover magnesium sulfate and concentrated in vacuo. Purification by silicagel chromatography, eluting with a solvent gradient of 98:2 to 4:1methylene chloride/methanol, provided 0.229 g of4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazoline as ayellow solid, mp 166-168° C.

¹HNMR (d⁶-DMSO): δ 8.97 (s, 1H); 8.78 (s, 1H); 8.50 (s, 1H); 7.75 (s,1H); 7.68 (s, 1H); 4.32 (t, 2H, J=4.4 Hz); 3.98 (s, 3H); 3.61 (t, 4H,J=3.5 Hz); 2.83 (t, 2H, J=4.3 Hz); 2.54 (m, 4H).

MS (ES, positive ion mode): m/z calcd for C₁₉H₂₀ClN₃O₃: 373.8, found(M+H)⁺ 374.2

Analysis for C₁₉H₂₀ClN₃O₃ Calcd: C, 61.04; H, 5.39; N, 11.24. Found: C,60.92; H, 5.16; N, 10.98.

EXAMPLE 32(4-Bromo-2-fluorophenyl)-[7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazolin-4-yl]-amine

To a suspension of 0.1 g (0.267 mmol) of4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazoline in 3mL of ethanol is added 0.061 g (0.321 mmol) of 4-bromo-2-fluoroanilineand 0.031 g (0.267 mmol) of pyridine hydrochloride. The mixture isbrought to reflux for 55 minutes, then allowed to cool to roomtemperature. A yellow precipitate formed, which is filtered and washedwith cold ethanol. Drying in vacuo provided 0.103 g of(4-bromo-2-fluorophenyl)-[7-methoxy-8-(2-morpholinyl-4-yl-ethoxy)benzo[g]quinazolin-4-yl]-aminedihydrochloride as a yellow solid, mp 210-225° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 12.02 (broad s, 1H); 11.45(broad s, 1H); 9.36 (s, 1H); 8.88 (s, 1H); 8.33 (s, 1H); 7.84 (s, 1H);7.80 (s, 1H); 7.60 (s, 2H); 7.44 (s, 1H); 4.71 (m, 2H); 4.02 (s, 3H);3.99 (m, 2H); 3.86 (m, 2H); 3.70 (m, 2H); 3.58 (m, 2H); 3.46 (m, 2H).

MS (ES, positive ion mode): m/z calcd for C₂₅H₂₄BrFN₄O₃: 527.4, found(M+H)⁺ 528.7

Analysis for C₂₅H₂₄BrFN₄O₃.2HCl.CH₃CH₂OH Calcd: C, 50.17; H, 4.99; N,8.67. Found: C, 50.23; H, 4.91; N, 8.32.

EXAMPLE 33(2,4-Dichloro-5-methoxyphenyl)-[7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazolin-4-yl]-amine

To a suspension of 0.05 g (0.133 mmol) of4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazoline in 2mL of isopropanol is added 0.031 g (0.161 mmol) of2,4-dichloro-5-methoxyaniline and 0.016 g (0.133 mmol) of pyridinehydrochloride. The mixture is brought to reflux for 2 hours, thenallowed to cool to room temperature. A yellow precipitate formed, whichis filtered and washed with cold isopropanol. Drying in vacuo provided0.030 g of(2,4-dichloro-5-methoxyphenyl)-[7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazolin-4-yl]-aminedihydrochloride as a yellow solid, mp 258-260° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 9.29 (s, 1H); 8.96 (s, 1H); 8.32(s, 1H); 7.84 (s, 1H); 7.82 (s, 1H); 7.51 (s, 2H); 4.68 (m, 2H); 4.06(s, 3H); 3.98 (m, 2H); 3.91 (s, 3H); 3.79-3.73 (m, 4H); 3.70-3.67 (m,2H); 3.40-3.33 (m, 2H).

MS (ES, positive ion mode): m/z calcd for C₂₆H₂₆Cl₂N₄O₄: 529.4, found(M+H)⁺ 528.8

Analysis for C₂₆H₂₆Cl₂N₄O₄.2HCl.4H₂O Calcd: C, 46.31; H, 5.38; N, 8.31.Found: C, 46.37; H, 5.17; N, 8.23.

EXAMPLE 34(3-Bromophenyl)-[7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazolin-4-yl]-amine

To a suspension of 0.1 g (0.267 mmol) of4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazoline in 3mL of isopropanol is added 0.055 g (0.321 mmol) of 3-bromoaniline and0.031 g (0.267 mmol) of pyridine hydrochloride. The mixture is broughtto reflux for 15 minutes, then allowed to cool to room temperature. Ayellow precipitate forms, which is filtered and washed with coldethanol. Drying in vacuo provided 0.131 g of(3-bromophenyl)-[7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazolin-4-yl]-aminedihydrochloride as a yellow solid, mp 266-269° C.

¹HNMR (d⁶-DMSO+trifluoroacetic acid): δ 9.36 (s, 1H); 9.07 (d, 1H, J=1.4Hz); 8.31 (s, 1H); 8.19 (d, 1H, J=1.2 Hz); 7.87 (d, 1H, J=5.3 Hz); 7.82(s, 1H); 7.59 (d, 1H, J=6 Hz); 7.53 (dd, 1H, J=1.8 Hz, J=5.9 Hz); 7.50(s, 1H); 4.70 (m, 2H); 4.06 (s, 3H); 4.04 (m, 2H); 3.84-3.78 (m, 4H);3.70-3.67 (m, 2H); 3.36 (t, 2H, J=6.8 Hz).

MS (ES, positive ion mode): m/z calcd for C₂₅H₂₅BrN₄O₃: 509.4, found(M+H)⁺ 509.1

Analysis for C₂₅H₂₅BrN₄O₃.2HCl.2.5H₂O Calcd: C, 47.86; H, 5.14; N, 8.93.Found: C, 47.68; H, 4.98; N, 8.82.

1. A process for the production of 6,7,8-substituted 3-amino-2-naphthoates or 3-amino-2-naphthonitriles of formula (A)

wherein E is cyano or E is an alkoxycarbonyl of 2-12 carbons, —CO₂-Ph, —CO₂-L, cycloalkoxycarbonyl of 4-12 carbons, alkenyloxycarbonyl of 3-12 carbons, cycloalkenyloxycarbonyl of 5-12 carbons, alkynyloxycarbonyl of 4-12 carbons, any of which may be substituted on a carbon atom with one or more R₆ groups; R₁, R₂ and R₃ are each, independently, hydrogen, halogen, hydroxy, amino, hydroxyamino, trifluoromethyl, trifluoromethoxy, mercapto, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-8 carbon atoms, alkylthio of 1-6 carbon atoms, cycloalkylthio of 3-8 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, alkenoyl of 3-7 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy, benzyl, alkylamino of 1-6 carbon atoms, alkanoyloxy of 2-7 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoyloxymethyl group of 2-7 carbon atoms, alkenoyloxymethyl group of 2-7 carbon atoms, alkynoyloxymethyl group of 2-7 carbon atoms, azido, benzoyl, carboxyalkyl of 2-7 carbons, carboalkoxyalkyl of 3-8 carbon atoms,

R₅ is independently hydrogen, alkyl of 1-6 carbon atoms, aminoalkyl of 1-6 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-12 carbon atoms, N-cycloalkylaminoalkyl of 4-12 carbon atoms, N-cycloalkyl-N-alkylaminoalkyl of 5-18 carbon atoms, N,N-dicycloalkylaminoalkyl of 7-18 carbon atoms, morpholino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, piperidino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, N-alkyl-piperazino-N-alkyl wherein either alkyl group is 1-6 carbon atoms, azacycloalkyl-N-alkyl of 3-11 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-8 carbon atoms, phenyl; V is (CH₂)_(m), O, S, or NR₆; R₇ is NR₆R₆, OR₆, J, N(R₆)₃ ⁺, or NR₆(OR₆); M is NR₆, O, S, N—[(C(R₆)₂)_(p)NR₆R₆], or N—[(C(R₆)₂)_(p)—OR₆]; W is NR₆, O, S, or is a bond; Het is a heterocycle selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane pyrrole, and tetrahydropyran; wherein the heterocycle is optionally mono- or di-substituted on carbon or nitrogen with R₆; optionally mono- or di-substituted on carbon with hydroxy, —N(R₆)₂, or —OR₆; optionally mono or di-substituted on carbon with the mono-valent radicals —(C(R₆)₂)_(s)OR₆ or —[(C(R₆)₂)_(s)N(R₆)₂]; or optionally mono or di-substituted on a saturated carbon with divalent radicals ═O or —O(C(R₆)₂)_(s)O—; Ph is a phenyl ring optionally mono-, di- or tri-substituted with halogen, alkyl of 1-6 carbon atoms, trifluoromethyl, nitro, cyano, azido, halomethyl, carboxyl, alkoxycarbonyl, alkylthio, mercapto, mercaptomethyl, —N(R₆)₂, —OR₆, —(C(R₆)₂)_(s)OR₆, —[(C(R₆)₂)_(s)N(R₆)₂], or —(C(R₆)₂)_(k)Het; R₆ is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, alkanoyl of 2-7 carbon atoms, carbamoylalkyl of 2-7 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxycycloalkyl of 3-6 carbon atoms, or carboxyalkyl of 2-7 carbon atoms; or R₆ is phenyl optionally mono-, di-, or tri-substituted with halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, alkoxycarbonyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino; alkanoylamino of 1-6 carbon atoms or alkyl of 1-6 carbon atoms; R₈ and R₉ are each, independently, —[(C(R₆)₂)_(r)NR₆R₆], or —[(C(R₆)₂)_(r)OR₆]; J is hydrogen, chlorine, fluorine, or bromine; L is a phenyl ring that is optionally substituted with one, two, or three substituent(s) independently selected from the group consisting of alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halogen, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; or L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatom(s) independently selected from N, O, and S and where the heteroaryl ring may be optionally mono- or di-substituted with substituent(s) independently selected from the group consisting of halogen, oxo, thiocarbonyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 16 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; g=1-6; k=0-4; p=2-4; q=0-4; r=1-4; s=1-6; m is 0-3; which process comprises: (a) reacting a substituted bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile of formula 1

wherein R₁, R₂, and R₃ are defined as above; with a base to form a first intermediate having the corresponding anion alpha to the cyano group; (b) reacting said first intermediate with a suitable electrophilic sulfur species to yield an alpha-sulfenylated 1-cyanobenzocyclobutene of formula 2

wherein R₁₀ is defined as an alkyl of 1-10 carbons, cycloalkyl of 3-10 carbons, alkenyl of 3-10 carbons, cycloalkenyl of 4-10 carbons, alkynyl of 3-10 carbons, Ph or L (where Ph and L are as hereinabove defined) and R₁, R₂, and R₃ are defined as above; (c) reacting said cyanobenzocyclobutenes of formula 2 with an anionic salt of acetonitrile or a compound of the formula

wherein E¹ is alkyl, phenyl, L, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, any of which may be substituted with one or more R₆ groups; wherein L and R₆ are defined as above; to provide an amino ester or intermediate of formula 3

wherein R₁, R₂, R₃, R₁₀, and E are defined as above; and (d) refluxing the formula 3 adducts in a solvent to provide the substituted ester of formula A.
 2. The process according to claim 1 wherein the base in step (a) is a strong base.
 3. The process according to claim 1 wherein R₁₀ is Ph.
 4. The process according to claim 1 wherein the temperature of the reaction in step (a) is a temperature of about 0° to about −100° C.
 5. The process according to claim 1 wherein the reaction in step (c) is a reaction of an anionic salt of an alkyl ester or acetonitrile with said cyanobenzocyclobutene.
 6. The process according to claim 1 wherein the suitable electrophilic sulfur species is an optionally substituted dialkyl disulfide or optionally substituted diphenyl disulfide.
 7. The process according to claim 6 wherein the disulfide electrophile is di-p-chlorophenyl disulfide. 